95 results on '"Tiosano D"'
Search Results
2. SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling
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Lin, Y.C., Niceta, M., Muto, V., Vona, B., Pagnamenta, A.T., Maroofian, R., Beetz, C., Duyvenvoorde, H. van, Dentici, M.L., Lauffer, P., Vallian, S., Ciolfi, A., Pizzi, S., Bauer, P., Gruning, N.M., Bellacchio, E., Fattore, A. del, Petrini, S., Shaheen, R., Tiosano, D., Halloun, R., Pode-Shakked ben, Albayrak, H.M., Isik, E., Wit, J.M., Dittrich, M., Freire, B.L., Bertola, D.R., Jorge, A.A.L., Barel, O., Sabir, A.H., Tenaiji, A.M.J. al, Taji, S.M., Al-Sannaa, N., Al-Abdulwahed, H., Digilio, M.C., Irving, M., Anikster, Y., Bhavani, G.S.L., Girisha, K.M., Haaf, T., Taylor, J.C., Dallapiccola, B., Alkuraya, F.S., Yang, R.B., Tartaglia, M., Genomics England Res Consortium, Consortium, Genomics England Research, Graduate School, Paediatric Endocrinology, ANS - Cellular & Molecular Mechanisms, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
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Male ,0301 basic medicine ,SCUBE ,Developmental Disabilities ,mechanism of disease ,Morphogenesis ,Bone Morphogenetic Protein 2 ,morphogenesis ,Bone Morphogenetic Protein 4 ,Biology ,Bone morphogenetic protein ,Bone morphogenetic protein 2 ,Article ,Bone and Bones ,Cell Line ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Osteogenesis ,Cell Line, Tumor ,bone morphogenetic protein ,Genetics ,Animals ,Humans ,BMP ,Receptor ,Genetics (clinical) ,Loss function ,Mice, Inbred C3H ,Calcium-Binding Proteins ,intracellular signaling ,Gene Expression Regulation, Developmental ,skeletal development ,Hep G2 Cells ,Chondrogenesis ,Phenotype ,Endochondral bone growth ,Cell biology ,Mice, Inbred C57BL ,HEK293 Cells ,030104 developmental biology ,Bone Morphogenetic Proteins ,genomic sequencing ,MCF-7 Cells ,Intercellular Signaling Peptides and Proteins ,Female ,BMP receptors ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
Summary Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a member of a small family of multifunctional cell surface-anchored glycoproteins functioning as co-receptors for a variety of growth factors. Here we report that bi-allelic inactivating variants in SCUBE3 have pleiotropic consequences on development and cause a previously unrecognized syndromic disorder. Eighteen affected individuals from nine unrelated families showed a consistent phenotype characterized by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies. In vitro functional validation studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, and their dysregulating effect on bone morphogenetic protein (BMP) signaling. We show that SCUBE3 acts as a BMP2/BMP4 co-receptor, recruits the BMP receptor complexes into raft microdomains, and positively modulates signaling possibly by augmenting the specific interactions between BMPs and BMP type I receptors. Scube3−/− mice showed craniofacial and dental defects, reduced body size, and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder. Our findings identify a human disease caused by defective function of a member of the SCUBE family, and link SCUBE3 to processes controlling growth, morphogenesis, and bone and teeth development through modulation of BMP signaling.
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- 2021
3. Pathogenic variants in SMARCA5, a chromatin remodeler, cause a range of syndromic neurodevelopmental features
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Li, D, Wang, Q, Gong, NN, Kurolap, A, Feldman, HB, Boy, N, Brugger, M, Grand, K, McWalter, K, Sacoto, MJG, Wakeling, E, Hurst, J, March, ME, Bhoj, EJ, Nowaczyk, MJM, Gonzaga-Jauregui, C, Mathew, M, Dava-Wala, A, Siemon, A, Bartholomew, D, Huang, Y, Lee, H, Martinez-Agosto, JA, Schwaibold, EMC, Brunet, T, Choukair, D, Pais, LS, White, SM, Christodoulou, J, Brown, D, Lindstrom, K, Grebe, T, Tiosano, D, Kayser, MS, Tan, TY, Deardorff, MA, Song, Y, Hakonarson, H, Li, D, Wang, Q, Gong, NN, Kurolap, A, Feldman, HB, Boy, N, Brugger, M, Grand, K, McWalter, K, Sacoto, MJG, Wakeling, E, Hurst, J, March, ME, Bhoj, EJ, Nowaczyk, MJM, Gonzaga-Jauregui, C, Mathew, M, Dava-Wala, A, Siemon, A, Bartholomew, D, Huang, Y, Lee, H, Martinez-Agosto, JA, Schwaibold, EMC, Brunet, T, Choukair, D, Pais, LS, White, SM, Christodoulou, J, Brown, D, Lindstrom, K, Grebe, T, Tiosano, D, Kayser, MS, Tan, TY, Deardorff, MA, Song, Y, and Hakonarson, H
- Abstract
Intellectual disability encompasses a wide spectrum of neurodevelopmental disorders, with many linked genetic loci. However, the underlying molecular mechanism for more than 50% of the patients remains elusive. We describe pathogenic variants in SMARCA5, encoding the ATPase motor of the ISWI chromatin remodeler, as a cause of a previously unidentified neurodevelopmental disorder, identifying 12 individuals with de novo or dominantly segregating rare heterozygous variants. Accompanying phenotypes include mild developmental delay, frequent postnatal short stature and microcephaly, and recurrent dysmorphic features. Loss of function of the SMARCA5 Drosophila ortholog Iswi led to smaller body size, reduced sensory dendrite complexity, and tiling defects in larvae. In adult flies, Iswi neural knockdown caused decreased brain size, aberrant mushroom body morphology, and abnormal locomotor function. Iswi loss of function was rescued by wild-type but not mutant SMARCA5. Our results demonstrate that SMARCA5 pathogenic variants cause a neurodevelopmental syndrome with mild facial dysmorphia.
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- 2021
4. A steroid metabolomic approach to 17α-hydroxylase/17,20 lyase deficiency
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Tiosano, D., Navon, R., Flor, O., Knopf, C., Hartmann, M. F., Wudy, S. A., Yakhini, Z., and Hochberg, Z.
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- 2010
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5. Endocrine complications of thalassemia
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Tiosano, D. and Hochberg, Z.
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- 2001
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6. Calcium metabolism
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Tiosano, D., primary, Hochberg, Z., additional, and Rogol, A.D., additional
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- 2007
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7. Maxillary tumour-induced osteomalacia
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Emodi, O., Rachmiel, A., Tiosano, D., and Nagler, R.M.
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- 2018
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8. Characterizing the steroidal milieu in amniotic fluid of mid-gestation: A GC-MS study
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Wang, R., primary, Hartmann, M.F., additional, Tiosano, D., additional, and Wudy, S.A., additional
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- 2019
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9. Characterizing the steroidal milieu in amniotic fluid of mid-gestation: A LC–MS/MS study
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Wang, R., primary, Tiosano, D., additional, Sánchez-Guijo, A., additional, Hartmann, M.F., additional, and Wudy, S.A., additional
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- 2019
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10. Identification and characterization of novel parathyroid-specific transcription factor Glial Cells Missing Homolog B (GCMB) mutations in eight families with autosomal recessive hypoparathyroidism
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Bowl, M. R., primary, Mirczuk, S. M., additional, Grigorieva, I. V., additional, Piret, S. E., additional, Cranston, T., additional, Southam, L., additional, Allgrove, J., additional, Bahl, S., additional, Brain, C., additional, Loughlin, J., additional, Mughal, Z., additional, Ryan, F., additional, Shaw, N., additional, Thakker, Y. V., additional, Tiosano, D., additional, Nesbit, M. A., additional, and Thakker, R. V., additional
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- 2010
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11. The hypothyroidism in an inbred kindred with congenital thyroid hormone and glucocorticoid deficiency is due to a mutation producing a truncated thyrotropin receptor.
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Tiosano, D, Pannain, Silvana, Vassart, Gilbert, Parma, Jasmine, Gershoni-Baruch, R, Mandel, H, Lotan, R, Zaharan, Y, Pery, M, Weiss, R E, Refetoff, Samuel, Hochberg, Z, Tiosano, D, Pannain, Silvana, Vassart, Gilbert, Parma, Jasmine, Gershoni-Baruch, R, Mandel, H, Lotan, R, Zaharan, Y, Pery, M, Weiss, R E, Refetoff, Samuel, and Hochberg, Z
- Abstract
Growth and function of the thyroid and adrenal glands are maintained and controlled by thyrotropin (TSH) and adrenocorticotrophic hormone (ACTH), respectively. The action of these trophic hormones requires the presence of functional TSH and ACTH receptors. We describe a large inbred Bedouin kindred in which profound congenital hypothyroidism and hypoadrenocortisolism occurred alone or together in eight family members belonging to four nuclear families. The high serum TSH and ACTH levels in the presence of normal or hypoplastic thyroid glands and low glucocorticoid, but not mineralocorticoid concentrations, are characteristic of resistance to TSH and ACTH. Linkage analysis, using specific polymorphic markers, excluded the involvement of the ACTH receptor but not thyrotropin receptor (TSHR). A novel point mutation was identified in exon 10 of the TSHR that replaces the normal cytosine in nucleotide 2024 with a thymidine. As a result the normal arginine in codon 609 (CGA) is replaced with a stop codon (TGA). This mutation produces a truncated TSHR lacking the third intracellular and extracellular loops, the sixth and seventh transmembrane segments, and the intracytoplasmic tail. The presence of hypothyroidism did not affect the timing, severity, and manner of clinical manifestation of hypoadrenocortisolism., Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., info:eu-repo/semantics/published
- Published
- 1999
12. Hypothalamic Regulation of Adiposity: The Role of 11β-Hydroxysteroid Dehydrogenase Type 1
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Hochberg, Z., primary, Friedberg, M., additional, Yaniv, L., additional, Bader, T., additional, and Tiosano, D., additional
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- 2004
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13. Evidence for oligogenic inheritance of type 1 diabetes in a large Bedouin Arab family.
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Verge, C F, primary, Vardi, P, additional, Babu, S, additional, Bao, F, additional, Erlich, H A, additional, Bugawan, T, additional, Tiosano, D, additional, Yu, L, additional, Eisenbarth, G S, additional, and Fain, P R, additional
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- 1998
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14. Melatonin replacement corrects sleep disturbances in a child with pineal tumor
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Etzioni, A., primary, Luboshitzky, R., additional, Tiosano, D., additional, Ben-Harush, M., additional, Goldsher, D., additional, and Lavie, P., additional
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- 1996
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15. Vitamin D action: lessons learned from hereditary 1,25-dihydroxyvitamin-D-resistant rickets patients.
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Tiosano D and Gepstein V
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- 2012
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16. The molecular basis of hereditary 1,25-dihydroxyvitamin D3 resistant rickets in seven related families.
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Malloy, P J, primary, Hochberg, Z, additional, Tiosano, D, additional, Pike, J W, additional, Hughes, M R, additional, and Feldman, D, additional
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- 1990
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17. Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations
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Villanueva C, Jacobson-Dickman E, Xu C, ManouvrierS, DwyerA, Sykiotis GP, Beenken A, Liu Y, Tommiska J, Hu Y, Tiosano D, Gerard M, Leger J, Drouin-Garraud V, Lefebvre H, Polak M, Carel J, Phan-Hug F, Hauschild M, Raivio T, Bouloux P, Sidis Y, Mohammadi M, de Roux N, and Pitteloud N
- Abstract
Purpose:Congenital hypogonadotropic hypogonadism (CHH) and split hand/foot malformation (SHFM) are two rare genetic conditions. Here we report a clinical entity comprising the two.Methods:We identified patients with CHH and SHFM through international collaboration. Probands and available family members underwent phenotyping and screening for FGFR1 mutations. The impact of identified mutations was assessed by sequence and structure based predictions and/or functional assays.Results:We identified eight probands with CHH with (n = 3; Kallmann syndrome) or without anosmia (n = 5) and SHFM seven of whom (88) harbor FGFR1 mutations. Of these seven one individual is homozygous for p.V429E and six individuals are heterozygous for p.G348R p.G485R p.Q594 p.E670A p.V688L or p.L712P. All mutations were predicted by in silico analysis to cause loss of function. Probands with FGFR1 mutations have severe gonadotropin releasing hormone deficiency (absent puberty and/or cryptorchidism and/or micropenis). SHFM in both hands and feet was observed only in the patient with the homozygous p.V429E mutation; V429 maps to the fibroblast growth factor receptor substrate 2a binding domain of FGFR1 and functional studies of the p.V429E mutation demonstrated that it decreased recruitment and phosphorylation of fibroblast growth factor receptor substrate 2a to FGFR1 thereby resulting in reduced mitogen activated protein kinase signaling.Conclusion:FGFR1 should be prioritized for genetic testing in patients with CHH and SHFM because the likelihood of a mutation increases from 10 in the general CHH population to 88 in these patients.Genet Med advance online publication 13 November 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.166.
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18. Severe hypersomnolence after pituitary/hypothalamic surgery in adolescents: clinical characteristics and potential mechanisms.
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Snow A, Gozal E, Malhotra A, Tiosano D, Perlman R, Vega C, Shahar E, Gozal D, Hochberg Z, and Pillar G
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- 2002
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19. Linear growth of children with X-linked hypophosphatemia treated with burosumab: a real-life observational study.
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Levy-Shraga Y, Levi S, Regev R, Gal S, Brener A, Lebenthal Y, Gillis D, Strich D, Zung A, Cleper R, Borovitz Y, Bello R, Tenenbaum A, Zadik Z, Davidovits M, Zeitlin L, and Tiosano D
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- Child, Humans, Infant, Child, Preschool, Adolescent, Antibodies, Monoclonal therapeutic use, Retrospective Studies, Phosphorus therapeutic use, Growth Hormone therapeutic use, Phosphates, Familial Hypophosphatemic Rickets drug therapy
- Abstract
To assess the long-term efficacy of burosumab for pediatric patients with X-linked hypophosphatemia, focusing on linear growth. This multi-center retrospective study included 35 pediatric patients who began treatment with burosumab between January 2018 and January 2021. We collected clinical data, anthropometric measurements, laboratory results, and Rickets Severity Score (RSS), from 2 years prior to treatment initiation and up to 4 years after. Burosumab was initiated at a mean age of 7.5 ± 4.4 years (range 0.6-15.9), with a mean initial dose of 0.8 ± 0.3 mg/kg, which was subsequently increased to 1.1 ± 0.4 mg/kg. The patients were followed for 2.9 ± 1.4 years (range 1-4) after initiating burosumab. Serum phosphorus levels increased from 2.7 ± 0.8 mg/dl at burosumab initiation to 3.4 ± 0.6 mg/dl after 3 months and remained stable (p < 0.001). Total reabsorption of phosphorus increased from 82.0 ± 6.8 to 90.1 ± 5.3% after 12 months of treatment (p = 0.041). The RSS improved from 1.7 ± 1.0 at burosumab initiation to 0.5 ± 0.6 and 0.3 ± 0.6 after 12 and 24 months, respectively (p < 0.001). Both height z-score and weight z-score improved from burosumab initiation to the end of the study: from - 2.07 ± 1.05 to - 1.72 ± 1.04 (p < 0.001) and from - 0.51 ± 1.12 to - 0.11 ± 1.29 (p < 0.001), respectively. Eight children received growth hormone combined with burosumab treatment. Height z-score improved among those who received growth hormone (from - 2.33 ± 1.12 to - 1.94 ± 1.24, p = 0.042) and among those who did not (from - 2.01 ± 1.01 to - 1.66 ± 1.01, p = 0.001)., Conclusion: Burosumab treatment in a real-life setting improved phosphate homeostasis and rickets severity and enhanced linear growth., What Is Known: • Compared to conventional therapy, burosumab treatment has been shown to increase serum phosphate levels and reduce the severity of rickets. • The effect of burosumab on growth is still being study., What Is New: • Height z-score improved between the start of burosumab treatment and the end of the study (-2.07 ± 1.05 vs. -1.72 ± 1.04, p < 0.001). • Eight children received burosumab combined with growth hormone treatment without side effects during the concomitant treatments., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2023
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20. The effect of etanercept therapy on adrenal steroid metabolism in juvenile idiopathic arthritis: a steroid metabolomics approach.
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Aviel YB, Keinan A, Hartmann MF, Wudy SA, and Tiosano D
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- Humans, Etanercept therapeutic use, Steroid 21-Hydroxylase, Steroids, Arthritis, Juvenile drug therapy, Hydrocortisone metabolism
- Abstract
Objective: To evaluate the impact of anti-tumor necrosis factor-alpha (TNFα: etanercept [Etanercept ®]) therapy on adrenal activity in juvenile idiopathic arthritis (JIA) ., Method: Eleven JIA patients aged 12 ± 6.2 years with a disease duration of 6.3 ± 5.2 years were enrolled. They were treated once weekly with etanercept (0.8 mg/kg) for 3 ± 2.8 years. Urine samples for gas chromatography-mass spectrometry steroid hormone analysis were collected before, and 1 and 3 days after etanercept injection and compared to age- and sex-matched healthy controls., Results: The levels of 21 of the 31 metabolites were low before etanercept treatment. Those 21 metabolites included 4 C19 steroids (androgens), 5 C C21 steroid hormone intermediates, 10 cortisol metabolites, and 2 corticosterone metabolites. One day after treatment, only 5 of the 21 metabolite levels remained low. They included 2 C19 metabolites, 2 C21 steroid metabolites and 1 cortisol metabolite β -Cortol (β-Cl). Three days after treatment, the only metabolites levels that continued to be low were 2 C19 metabolite, 2 C21 steroid hormone intermediates and 1 cortisol metabolite α-Cortol (a-Cl), while the remaining 15 metabolites had already normalized after 1 day. Dehydroepiandrosterone-sulfate and 17-hydroxypregnenolone metabolite levels were the last ones to recover. Urinary metabolite ratios reflecting cytochrome P450 CYP21A2 (21-hydroxylase) and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) enzymatic activitieswere lower in JIA patients than in controls, although significant was not reached., Conclusion: Almost all of the pre-etanercept treatment cortisol urinary metabolite levels were significantly lower than normal, and almost all rose to normal values by 1 day after treatment. The therapeutic effect of anti-TNFα treatment in JIA may be related to its effect on the restoration of adrenal function and cortisol levels., (© 2023. The Author(s).)
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- 2023
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21. An Expert Perspective on Phosphate Dysregulation With a Focus on Chronic Hypophosphatemia.
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Aljuraibah F, Bacchetta J, Brandi ML, Florenzano P, Javaid MK, Mäkitie O, Raimann A, Rodriguez M, Siggelkow H, Tiosano D, Vervloet M, and Wagner CA
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- Adolescent, Adult, Fibroblast Growth Factors therapeutic use, Humans, Phosphates, Quality of Life, Familial Hypophosphatemic Rickets drug therapy, Hypophosphatemia, Osteomalacia drug therapy
- Abstract
Because of their rarity, diseases characterized by chronic hypophosphatemia can be underrecognized and suboptimally managed, resulting in poor clinical outcomes. Moreover, serum phosphate may not be measured routinely in primary care practice. Authors participated in several working sessions to advance the understanding of phosphate homeostasis and the causes, consequences, and clinical implications of chronic hypophosphatemia. Phosphate levels are regulated from birth to adulthood. Dysregulation of phosphate homeostasis can result in hypophosphatemia, which becomes chronic if phosphate levels cannot be normalized. Chronic hypophosphatemia may be underrecognized as serum phosphate measurement is not always part of routine analysis in the primary care setting and results might be misinterpreted, for instance, due to age-specific differences not being accounted for and circadian variations. Clinical consequences of chronic hypophosphatemia involve disordered endocrine regulation, affect multiple organ systems, and vary depending on patient age and the underlying disorder. Signs and symptoms of chronic hypophosphatemic diseases that manifest during childhood or adolescence persist into adulthood if the disease is inadequately managed, resulting in an accumulation of clinical deficits and a progressive, debilitating impact on quality of life. Early identification and diagnosis of patients with chronic hypophosphatemia is crucial, and clinical management should be started as soon as possible to maximize the likelihood of improving health outcomes. Furthermore, in the absence of a universally accepted description for "chronic hypophosphatemia," a definition is proposed here that aims to raise awareness of these diseases, facilitate diagnosis, and guide optimal phosphate management strategies by improving monitoring and assessment of patient response to treatment. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)
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- 2022
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22. PI(3,4)P2-mediated cytokinetic abscission prevents early senescence and cataract formation.
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Gulluni F, Prever L, Li H, Krafcikova P, Corrado I, Lo WT, Margaria JP, Chen A, De Santis MC, Cnudde SJ, Fogerty J, Yuan A, Massarotti A, Sarijalo NT, Vadas O, Williams RL, Thelen M, Powell DR, Schueler M, Wiesener MS, Balla T, Baris HN, Tiosano D, McDermott BM Jr, Perkins BD, Ghigo A, Martini M, Haucke V, Boura E, Merlo GR, Buchner DA, and Hirsch E
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- Aging, Premature, Animals, Biological Evolution, Calcium-Binding Proteins metabolism, Cataract metabolism, Cell Cycle Proteins metabolism, Cell Line, Humans, Lens, Crystalline growth & development, Lens, Crystalline metabolism, Mice, Mutation, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 4,5-Diphosphate metabolism, Tubulin metabolism, Zebrafish, Zebrafish Proteins genetics, Zebrafish Proteins metabolism, Cataract pathology, Cellular Senescence, Cytokinesis, Endosomal Sorting Complexes Required for Transport metabolism, Lens, Crystalline cytology, Phosphatidylinositol 3-Kinases metabolism, Phosphatidylinositols metabolism
- Abstract
Cytokinetic membrane abscission is a spatially and temporally regulated process that requires ESCRT (endosomal sorting complexes required for transport)–dependent control of membrane remodeling at the midbody, a subcellular organelle that defines the cleavage site. Alteration of ESCRT function can lead to cataract, but the underlying mechanism and its relation to cytokinesis are unclear. We found a lens-specific cytokinetic process that required PI3K-C2α (phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2α), its lipid product PI(3,4)P
2 (phosphatidylinositol 3,4-bisphosphate), and the PI(3,4)P2 –binding ESCRT-II subunit VPS36 (vacuolar protein-sorting-associated protein 36). Loss of each of these components led to impaired cytokinesis, triggering premature senescence in the lens of fish, mice, and humans. Thus, an evolutionarily conserved pathway underlies the cell type–specific control of cytokinesis that helps to prevent early onset cataract by protecting from senescence.- Published
- 2021
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23. Expanding the spectrum of endocrinopathies identified in Schaaf-Yang syndrome - A case report and review of the literature.
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Halloun R, Habib C, Ekhilevitch N, Weiss R, Tiosano D, and Cohen M
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- Developmental Disabilities drug therapy, Developmental Disabilities pathology, Diazoxide therapeutic use, Female, Humans, Hyperinsulinism drug therapy, Hyperinsulinism pathology, Infant, Insulin blood, Mutation, Syndrome, Developmental Disabilities genetics, Hyperinsulinism genetics, Phenotype, Proteins genetics
- Abstract
Schaaf-Yang syndrome is a genetic disorder caused by mutations in the paternal allele of the MAGEL2 gene. Developmental delay, feeding difficulties, joint contractures and a high prevalence of autism spectrum disorders are characteristic of the syndrome. Endocrine abnormalities include mostly various pituitary hormonal deficiencies, presenting as hypoglycemia in 48% of reported cases. Persistent hyperinsulinism was only described in two siblings and responded to diazoxide treatment. We describe a unique case of an infant with Schaaf-Yang syndrome that presented with persistent hyperinsulinism unresponsive to diazoxide. Furthermore, we conducted a literature review of the endocrine abnormalities described in MAGEL2 related disorders. The case presented expands the clinical phenotype of Schaaf-Yang syndrome and emphasizes the importance of endocrine follow-up in these patients. Further investigation into the role of MAGEL2 in the regulation of pancreatic beta-cell insulin secretion, will improve our understanding of the abnormalities in glucose regulation in this syndrome., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
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- 2021
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24. Pathogenic variants in SMARCA5 , a chromatin remodeler, cause a range of syndromic neurodevelopmental features.
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Li D, Wang Q, Gong NN, Kurolap A, Feldman HB, Boy N, Brugger M, Grand K, McWalter K, Guillen Sacoto MJ, Wakeling E, Hurst J, March ME, Bhoj EJ, Nowaczyk MJM, Gonzaga-Jauregui C, Mathew M, Dava-Wala A, Siemon A, Bartholomew D, Huang Y, Lee H, Martinez-Agosto JA, Schwaibold EMC, Brunet T, Choukair D, Pais LS, White SM, Christodoulou J, Brown D, Lindstrom K, Grebe T, Tiosano D, Kayser MS, Tan TY, Deardorff MA, Song Y, and Hakonarson H
- Abstract
Intellectual disability encompasses a wide spectrum of neurodevelopmental disorders, with many linked genetic loci. However, the underlying molecular mechanism for more than 50% of the patients remains elusive. We describe pathogenic variants in SMARCA5 , encoding the ATPase motor of the ISWI chromatin remodeler, as a cause of a previously unidentified neurodevelopmental disorder, identifying 12 individuals with de novo or dominantly segregating rare heterozygous variants. Accompanying phenotypes include mild developmental delay, frequent postnatal short stature and microcephaly, and recurrent dysmorphic features. Loss of function of the SMARCA5 Drosophila ortholog Iswi led to smaller body size, reduced sensory dendrite complexity, and tiling defects in larvae. In adult flies, Iswi neural knockdown caused decreased brain size, aberrant mushroom body morphology, and abnormal locomotor function. Iswi loss of function was rescued by wild-type but not mutant SMARCA5. Our results demonstrate that SMARCA5 pathogenic variants cause a neurodevelopmental syndrome with mild facial dysmorphia., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)
- Published
- 2021
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25. Lessons Learned from Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets Patients on Vitamin D Functions.
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Tiosano D, Abrams SA, and Weisman Y
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- Adolescent, Adult, Animals, Asthma genetics, Asthma immunology, Blood Pressure physiology, Bone Density physiology, Bone and Bones metabolism, Bronchial Hyperreactivity genetics, Bronchial Hyperreactivity immunology, Calcium metabolism, Child, Child, Preschool, Cytokines blood, Disease Models, Animal, Female, Genitalia, Female physiology, Genitalia, Male physiology, Humans, Infant, Intestinal Absorption, Male, Mice, Mice, Knockout, Renin-Angiotensin System physiology, Young Adult, Codon, Nonsense, Familial Hypophosphatemic Rickets immunology, Receptors, Calcitriol genetics
- Abstract
We summarize here lessons learned from studies on skeletal and extra-skeletal functions of vitamin D in hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) patients with a mutant, nonfunctioning vitamin D receptor (VDR). During childhood, HVDRR patients are dependent on intestinal VDR, demonstrate low intestinal fraction calcium absorption, and have a bone calcium accretion rate that leads to hypocalcemia and rickets. After puberty, there is recovery in intestinal calcium absorption and in bone calcium accretion and structure. HVDRR monocytes and lymphocytes show impairment in the expression of antimicrobial proteins and demonstrate a proinflammatory cytokine profile. However, HVDRR patients do not exhibit increased rates of infections or inflammatory diseases. Vitamin D deficiency is associated with asthmatic exacerbations. Surprisingly, HVDRR patients do not usually develop asthma. They have normal allergic tests and lung functions and are protected against provoked bronchial hyperactivity. HVDRR patients have decreased IL-5 levels in their exhaled breath condensate. Given that IL-5 is a key cytokine in the development of airway inflammation and hyperactivity and that VDR is important for IL-5 generation, it is plausible that low lung IL-5 protects HVDRR patients from asthma. Vitamin D metabolites have suppressive effects on the renin angiotensin system. However, no HVDRR patient showed hypertension or echocardiographic pathology, and their renin angiotensin metabolites were normal. The VDR is expressed throughout the reproductive system, suggesting a role in reproduction. However, the reproductive history of HVDRR patients is normal despite the lack of a normal VDR. HVDRR patients provide a unique opportunity to study the role of the VDR and the role of vitamin D in various human systems., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)
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- 2021
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26. SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling.
- Author
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Lin YC, Niceta M, Muto V, Vona B, Pagnamenta AT, Maroofian R, Beetz C, van Duyvenvoorde H, Dentici ML, Lauffer P, Vallian S, Ciolfi A, Pizzi S, Bauer P, Grüning NM, Bellacchio E, Del Fattore A, Petrini S, Shaheen R, Tiosano D, Halloun R, Pode-Shakked B, Albayrak HM, Işık E, Wit JM, Dittrich M, Freire BL, Bertola DR, Jorge AAL, Barel O, Sabir AH, Al Tenaiji AMJ, Taji SM, Al-Sannaa N, Al-Abdulwahed H, Digilio MC, Irving M, Anikster Y, Bhavani GSL, Girisha KM, Haaf T, Taylor JC, Dallapiccola B, Alkuraya FS, Yang RB, and Tartaglia M
- Subjects
- Animals, Bone Morphogenetic Protein 2 metabolism, Bone Morphogenetic Protein 4 metabolism, Bone Morphogenetic Proteins metabolism, Cell Line, Cell Line, Tumor, Female, Gene Expression Regulation, Developmental physiology, HEK293 Cells, Hep G2 Cells, Humans, Intercellular Signaling Peptides and Proteins metabolism, MCF-7 Cells, Male, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Bone and Bones metabolism, Calcium-Binding Proteins metabolism, Developmental Disabilities metabolism, Osteogenesis physiology, Signal Transduction physiology
- Abstract
Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a member of a small family of multifunctional cell surface-anchored glycoproteins functioning as co-receptors for a variety of growth factors. Here we report that bi-allelic inactivating variants in SCUBE3 have pleiotropic consequences on development and cause a previously unrecognized syndromic disorder. Eighteen affected individuals from nine unrelated families showed a consistent phenotype characterized by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies. In vitro functional validation studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, and their dysregulating effect on bone morphogenetic protein (BMP) signaling. We show that SCUBE3 acts as a BMP2/BMP4 co-receptor, recruits the BMP receptor complexes into raft microdomains, and positively modulates signaling possibly by augmenting the specific interactions between BMPs and BMP type I receptors. Scube3
-/- mice showed craniofacial and dental defects, reduced body size, and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder. Our findings identify a human disease caused by defective function of a member of the SCUBE family, and link SCUBE3 to processes controlling growth, morphogenesis, and bone and teeth development through modulation of BMP signaling., (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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27. COG6-CDG: Expanding the phenotype with emphasis on glycosylation defects involved in the causation of male disorders of sex development.
- Author
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Mandel H, Cohen Kfir N, Fedida A, Shuster Biton E, Odeh M, Kalfon L, Ben-Harouch S, Fleischer Sheffer V, Hoffman Y, Goldberg Y, Dinwiddie A, Dumin E, Eran A, Apel-Sarid L, Tiosano D, and Falik-Zaccai TC
- Subjects
- Congenital Disorders of Glycosylation mortality, Congenital Disorders of Glycosylation physiopathology, Disorders of Sex Development mortality, Disorders of Sex Development physiopathology, Female, Glycosylation, Homozygote, Humans, Infant, Newborn, Male, Mutation genetics, Phenotype, Sequence Deletion genetics, Siblings, Exome Sequencing, Adaptor Proteins, Vesicular Transport genetics, Congenital Disorders of Glycosylation genetics, Disorders of Sex Development genetics, Mixed Function Oxygenases genetics
- Abstract
COG6-congenital disorder of glycosylation (COG6-CDG) is caused by biallelic mutations in COG6. To-date, 12 variants causing COG6-CDG in less than 20 patients have been reported. Using whole exome sequencing we identified two siblings with a novel homozygous deletion of 26 bp in COG6, creating a splicing variant (c.518_540 + 3del) and a shift in the reading frame. The phenotype of COG6-CDG includes growth and developmental retardation, microcephaly, liver and gastrointestinal disease, hypohydrosis and recurrent infections. We report two patients with novel phenotypic features including bowel malrotation and ambiguous genitalia, directing attention to the role of glycoprotein metabolism in the causation of disorders of sex development (DSD). Searching the glycomic literature, we identified 14 CDGs including males with DSD, a feature not previously accentuated. This study broadens the genetic and phenotypic spectrum of COG6-CDG and calls for increasing awareness to the central role of glycosylation processes in development of human sex and genitalia., (© 2020 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)
- Published
- 2020
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28. In Silico Structural and Biochemical Functional Analysis of a Novel CYP21A2 Pathogenic Variant.
- Author
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Cohen M, Pignatti E, Dines M, Mory A, Ekhilevitch N, Kolodny R, Flück CE, and Tiosano D
- Subjects
- Child, Preschool, Evolution, Molecular, Female, Humans, Infant, Infant, Newborn, Computer Simulation, Mutation genetics, Steroid 21-Hydroxylase chemistry, Steroid 21-Hydroxylase genetics
- Abstract
Classical congenital adrenal hyperplasia (CAH) caused by pathogenic variants in the steroid 21-hydroxylase gene ( CYP21A2 ) is a severe life-threatening condition. We present a detailed investigation of the molecular and functional characteristics of a novel pathogenic variant in this gene. The patient, 46 XX newborn, was diagnosed with classical salt wasting CAH in the neonatal period after initially presenting with ambiguous genitalia. Multiplex ligation-dependent probe analysis demonstrated a full deletion of the paternal CYP21A2 gene, and Sanger sequencing revealed a novel de novo CYP21A2 variant c.694-696del ( E232del ) in the other allele. This variant resulted in the deletion of a non-conserved single amino acid, and its functional relevance was initially undetermined. We used both in silico and in vitro methods to determine the mechanistic significance of this mutation. Computational analysis relied on the solved structure of the protein (Protein-data-bank ID 4Y8W), structure prediction of the mutated protein, evolutionary analysis, and manual inspection. We predicted impaired stability and functionality of the protein due to a rotatory disposition of amino acids in positions downstream of the deletion. In vitro biochemical evaluation of enzymatic activity supported these predictions, demonstrating reduced protein levels to 22% compared to the wild-type form and decreased hydroxylase activity to 1-4%. This case demonstrates the potential of combining in-silico analysis based on evolutionary information and structure prediction with biochemical studies. This approach can be used to investigate other genetic variants to understand their potential effects.
- Published
- 2020
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29. Primary Ovarian Insufficiency Nationwide Incidence Rate and Etiology Among Israeli Adolescents.
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Gruber N, Kugler S, de Vries L, Brener A, Zung A, Eyal O, Rachmiel M, Koren I, Tenenbaum-Rakover Y, Hershkovitz E, Landau Z, Oren M, Eliakim A, Zangen D, German A, Majdoub H, Mazor-Aronovitch K, Modan-Moses D, Yeshayahu Y, Naugolni L, Levy-Shraga Y, Ben-Ami M, Brill G, Zuckerman-Levin N, Levy-Khademi F, Avnon-Ziv C, Tiosano D, Harel S, Kedem E, Segev-Becker A, Shoenfeld Y, and Pinhas-Hamiel O
- Subjects
- Adolescent, Adult, Amenorrhea epidemiology, Amenorrhea etiology, Child, Female, Follicle Stimulating Hormone, Humans, Incidence, Israel epidemiology, Young Adult, Primary Ovarian Insufficiency epidemiology, Primary Ovarian Insufficiency etiology
- Abstract
Purpose: The aim of the study was to estimate the current incidence and the distribution of etiologies of primary ovarian insufficiency (POI) in a nationwide study. The prevalence of POI in young adult women has recently increased, but the data cited for adolescents are more than three decades old., Methods: Data regarding females aged <21 years diagnosed with POI during the years 2000-2016 were collected from all the pediatric endocrinology units in Israel. POI was defined by at least 4 months of amenorrhea in association with menopausal levels of follicle-stimulating hormone. Iatrogenic cases were excluded., Results: For the 130 females aged <21 years included in the study, the distribution of POI etiologies was Turner syndrome/mosaicism in 56 (43%), idiopathic in 35 (27%), and other (developmental, genetic, metabolic, adrenal, and autoimmune) in 39 (30%) females. During the years 2009-2016, compared with 2000-2008, the incidence rate of new POI diagnoses per 100,000 person-years doubled (4.5 vs. 2.0; p value <.0001), and incidence rates of idiopathic and other etiologies increased by 2.6 (p value = .008) and 3.0 (p value = .002), respectively. In contrast, the incidence of Turner syndrome was constant (p value = .2). In the age group of 15-21 years, the current incidence of non-Turner POI in adolescents is one per 100,000 person-years., Conclusions: In this nationwide study, the incidence rate of POI in youth aged <21 years was one tenth of the rate that is commonly cited. A significant increase in the rate of POI in non-Turner females was observed over the last decade. Contributions of environmental and epigenetic factors should be studied., (Copyright © 2019 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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30. Mitochondrial Dysfunction in Primary Ovarian Insufficiency.
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Tiosano D, Mears JA, and Buchner DA
- Subjects
- Female, Gene Expression Regulation, Humans, Infertility, Female metabolism, Mitochondrial Diseases physiopathology, Primary Ovarian Insufficiency metabolism
- Abstract
Primary ovarian insufficiency (POI) is defined by the loss or dysfunction of ovarian follicles associated with amenorrhea before the age of 40. Symptoms include hot flashes, sleep disturbances, and depression, as well as reduced fertility and increased long-term risk of cardiovascular disease. POI occurs in ∼1% to 2% of women, although the etiology of most cases remains unexplained. Approximately 10% to 20% of POI cases are due to mutations in a single gene or a chromosomal abnormality, which has provided considerable molecular insight into the biological underpinnings of POI. Many of the genes for which mutations have been associated with POI, either isolated or syndromic cases, function within mitochondria, including MRPS22, POLG, TWNK, LARS2, HARS2, AARS2, CLPP, and LRPPRC. Collectively, these genes play roles in mitochondrial DNA replication, gene expression, and protein synthesis and degradation. Although mutations in these genes clearly implicate mitochondrial dysfunction in rare cases of POI, data are scant as to whether these genes in particular, and mitochondrial dysfunction in general, contribute to most POI cases that lack a known etiology. Further studies are needed to better elucidate the contribution of mitochondria to POI and determine whether there is a common molecular defect in mitochondrial function that distinguishes mitochondria-related genes that when mutated cause POI vs those that do not. Nonetheless, the clear implication of mitochondrial dysfunction in POI suggests that manipulation of mitochondrial function represents an important therapeutic target for the treatment or prevention of POI., (Copyright © 2019 Endocrine Society.)
- Published
- 2019
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31. Germline USP8 Mutation Associated With Pediatric Cushing Disease and Other Clinical Features: A New Syndrome.
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Cohen M, Persky R, Stegemann R, Hernández-Ramírez LC, Zeltser D, Lodish MB, Chen A, Keil MF, Tatsi C, Faucz FR, Buchner DA, Stratakis CA, and Tiosano D
- Subjects
- Abnormalities, Multiple genetics, Abnormalities, Multiple pathology, Adolescent, Developmental Disabilities complications, Developmental Disabilities genetics, Developmental Disabilities pathology, Female, Humans, Phenotype, Pituitary ACTH Hypersecretion pathology, Syndrome, Endopeptidases genetics, Endosomal Sorting Complexes Required for Transport genetics, Germ-Line Mutation, Pituitary ACTH Hypersecretion complications, Pituitary ACTH Hypersecretion genetics, Ubiquitin Thiolesterase genetics
- Abstract
Background: Somatic mutations in the ubiquitin-specific peptidase 8 (USP8) gene are common in corticotropinomas of children with Cushing disease (CD). We report a unique patient with a germline USP8 mutation who presented with CD and a constellation of other findings that constitute an intriguing genetic syndrome., Case Description: We describe a 16-year-old female with CD, developmental delay, dysmorphic features, ichthyosiform hyperkeratosis, chronic lung disease, chronic kidney disease, hyperglycemia, dilated cardiomyopathy with congestive heart failure, and previous history of hyperinsulinism and partial GH deficiency. She was diagnosed with CD at 14 years old and underwent transsphenoidal surgery. Despite initial improvement, she developed recurrent CD., Methods: DNA was extracted from peripheral blood and tumor DNA; whole-exome and Sanger confirmatory sequencing were performed. Immunohistochemistry was performed on the resected adenoma., Results: A de novo germline heterozygous USP8 mutation (c.2155T>C, p.S719P) in the critical 14-3-3 binding motif hot spot locus of the gene was identified in both the peripheral blood and tumor DNA. Histopathologic evaluation of the resected tumor confirmed an ACTH-secreting adenoma., Conclusion: Somatic USP8 mutations are common in adenomas causing CD, but to date, no germline defects have been reported. We describe a patient with a de novo germline USP8 mutation with recurrent CD and multiple other medical problems. This unique patient informs us of the multitude of signaling events that may be controlled by USP8., (Published by Oxford University Press on behalf of the Endocrine Society 2019.)
- Published
- 2019
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32. Combined Gestational Age- and Birth Weight-Adjusted Cutoffs for Newborn Screening of Congenital Adrenal Hyperplasia.
- Author
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Pode-Shakked N, Blau A, Pode-Shakked B, Tiosano D, Weintrob N, Eyal O, Zung A, Levy-Khademi F, Tenenbaum-Rakover Y, Zangen D, Gillis D, Pinhas-Hamiel O, Loewenthal N, de Vries L, Landau Z, Rachmiel M, Abu-Libdeh A, Eliakim A, Strich D, Koren I, German A, Sack J, and Almashanu S
- Subjects
- Cross-Sectional Studies, False Positive Reactions, Female, Humans, Infant, Newborn, Male, Pilot Projects, Adrenal Hyperplasia, Congenital diagnosis, Birth Weight, Gestational Age, Neonatal Screening
- Abstract
Context: Congenital adrenal hyperplasia (CAH) was among the first genetic disorders included in newborn screening (NBS) programs worldwide, based on 17α-hydroxyprogesterone (17-OHP) levels in dried blood spots. However, the success of NBS for CAH is hampered by high false positive (FP) rates, especially in preterm and low-birthweight infants., Objective: To establish a set of cutoff values adjusting for both gestational age (GA) and birthweight (BW), with the aim of reducing FP rates., Design: This cross-sectional, population-based study summarizes 10 years of experience of the Israeli NBS program for diagnosis of CAH. Multitiered 17-OHP cutoff values were stratified according to both BW and GA., Participants: A total of 1,378,132 newborns born between 2008 and 2017 were included in the NBS program., Results: Eighty-eight newborns were ultimately diagnosed with CAH; in 84 of these, CAH was detected upon NBS. The combined parameters-adjusted approach significantly reduced the recall FP rate (0.03%) and increased the positive predictive value (PPV) (16.5%). Sensitivity among those referred for immediate attention increased significantly (94%). There were four false negative cases (sensitivity, 95.4%), all ultimately diagnosed as simple-virilizing. Sensitivity and specificity were 95.4% and 99.9%, respectively, and the percentage of true-positive cases from all newborns referred for evaluation following a positive NBS result was 96%., Conclusions: The use of cutoff values adjusted for both GA and BW significantly reduced FP rates (0.03%) and increased overall PPV (16.5%). Based on our 10 years of experience, we recommend the implementation of this two parameter-adjusted approach for NBS of classic CAH in NBS programs worldwide., (Copyright © 2019 Endocrine Society.)
- Published
- 2019
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33. Reproductive history of patients with hereditary 1,25-dihydroxyvitamin D-resistant rickets.
- Author
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Tiosano D and Weisman Y
- Subjects
- Adult, Familial Hypophosphatemic Rickets complications, Familial Hypophosphatemic Rickets diagnosis, Familial Hypophosphatemic Rickets genetics, Female, Genetic Predisposition to Disease, Health Status, Humans, Male, Mutation, Phenotype, Pregnancy, Receptors, Calcitriol genetics, Retrospective Studies, Young Adult, Familial Hypophosphatemic Rickets physiopathology, Reproduction genetics, Reproductive Health
- Abstract
Objective: To study the reproductive history of patients with hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) who have a nonfunctioning vitamin D receptor (VDR)., Design: Retrospective cohort study., Setting: Tertiary university-affiliated medical center., Patient(s): Sixteen HVDRR patients and six spouses, four female and two male., Intervention(s): None., Main Outcome Measure(s): The data on age at menarche, time of conception, and number of pregnancies, abortions, and healthy newborns as reported by HVDRR women and partners of HVDRR men were analyzed, as were the results of semen sample analyses from HVDRR men., Result(s): All 16 patients had normal puberty. The mean age at menarche was 13.8 ± 0.8 years. Two married HVDRR women reported four normal pregnancies and four healthy newborns. Four married HVDRR men reported 15 pregnancies and nine healthy newborns. The wives of two of these men, who are brothers, gave birth to three healthy newborns and had six natural miscarriages during the second trimester of pregnancy. Time to conceive for all the female study patients was <1 year. Analysis of semen from the four men showed normal parameters., Conclusion(s): The VDR is expressed throughout the organs of reproduction, suggesting a role for vitamin D in reproduction. However, the reproductive potential of HVDRR patients with a mutant VDR gene with a nonfunctioning VDR appears to be normal., (Copyright © 2019 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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34. Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction.
- Author
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Tiosano D, Baris HN, Chen A, Hitzert MM, Schueler M, Gulluni F, Wiesener A, Bergua A, Mory A, Copeland B, Gleeson JG, Rump P, van Meer H, Sival DA, Haucke V, Kriwinsky J, Knaup KX, Reis A, Hauer NN, Hirsch E, Roepman R, Pfundt R, Thiel CT, Wiesener MS, Aslanyan MG, and Buchner DA
- Subjects
- Adolescent, Adult, Child, Consanguinity, Female, Fibroblasts metabolism, Humans, Male, Pedigree, Phenotype, Young Adult, Bone Diseases, Developmental genetics, Cataract genetics, Ciliary Motility Disorders genetics, Dwarfism genetics, Mutation, Phosphatidylinositol 3-Kinases genetics
- Abstract
PIK3C2A is a class II member of the phosphoinositide 3-kinase (PI3K) family that catalyzes the phosphorylation of phosphatidylinositol (PI) into PI(3)P and the phosphorylation of PI(4)P into PI(3,4)P2. At the cellular level, PIK3C2A is critical for the formation of cilia and for receptor mediated endocytosis, among other biological functions. We identified homozygous loss-of-function mutations in PIK3C2A in children from three independent consanguineous families with short stature, coarse facial features, cataracts with secondary glaucoma, multiple skeletal abnormalities, neurological manifestations, among other findings. Cellular studies of patient-derived fibroblasts found that they lacked PIK3C2A protein, had impaired cilia formation and function, and demonstrated reduced proliferative capacity. Collectively, the genetic and molecular data implicate mutations in PIK3C2A in a new Mendelian disorder of PI metabolism, thereby shedding light on the critical role of a class II PI3K in growth, vision, skeletal formation and neurological development. In particular, the considerable phenotypic overlap, yet distinct features, between this syndrome and Lowe's syndrome, which is caused by mutations in the PI-5-phosphatase OCRL, highlight the key role of PI metabolizing enzymes in specific developmental processes and demonstrate the unique non-redundant functions of each enzyme. This discovery expands what is known about disorders of PI metabolism and helps unravel the role of PIK3C2A and class II PI3Ks in health and disease., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2019
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35. Mutations in the mitochondrial ribosomal protein MRPS22 lead to primary ovarian insufficiency.
- Author
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Chen A, Tiosano D, Guran T, Baris HN, Bayram Y, Mory A, Shapiro-Kulnane L, Hodges CA, Akdemir ZC, Turan S, Jhangiani SN, van den Akker F, Hoppel CL, Salz HK, Lupski JR, and Buchner DA
- Subjects
- Adolescent, Adult, Amenorrhea genetics, Amenorrhea pathology, Animals, Disease Models, Animal, Drosophila genetics, Female, Fertility physiology, Homozygote, Humans, Menopause, Premature genetics, Mutation, Missense genetics, Ovarian Follicle pathology, Primary Ovarian Insufficiency pathology, Young Adult, Drosophila Proteins genetics, Fertility genetics, Mitochondrial Proteins genetics, Primary Ovarian Insufficiency genetics, Ribosomal Proteins genetics
- Abstract
Primary ovarian insufficiency (POI) is characterized by amenorrhea and loss or dysfunction of ovarian follicles prior to the age of 40. POI has been associated with autosomal recessive mutations in genes involving hormonal signaling and folliculogenesis, however, the genetic etiology of POI most often remains unknown. Here we report MRPS22 homozygous missense variants c.404G>A (p.R135Q) and c.605G>A (p.R202H) identified in four females from two independent consanguineous families as a novel genetic cause of POI in adolescents. Both missense mutations identified in MRPS22 are rare, occurred in highly evolutionarily conserved residues, and are predicted to be deleterious to protein function. In contrast to prior reports of mutations in MRPS22 associated with severe mitochondrial disease, the POI phenotype is far less severe. Consistent with this genotype-phenotype correlation, mitochondrial defects in oxidative phosphorylation or rRNA levels were not detected in fibroblasts derived from the POI patients, suggesting a non-bioenergetic or tissue-specific mitochondrial defect. Furthermore, we demonstrate in a Drosophila model that mRpS22 deficiency specifically in somatic cells of the ovary had no effect on fertility, whereas flies with mRpS22 deficiency specifically in germ cells were infertile and agametic, demonstrating a cell autonomous requirement for mRpS22 in germ cell development. These findings collectively identify that MRPS22, a component of the small mitochondrial ribosome subunit, is critical for ovarian development and may therefore provide insight into the pathophysiology and treatment of ovarian dysfunction.
- Published
- 2018
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36. Early-Onset Obesity: Unrecognized First Evidence for GNAS Mutations and Methylation Changes.
- Author
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Grüters-Kieslich A, Reyes M, Sharma A, Demirci C, DeClue TJ, Lankes E, Tiosano D, Schnabel D, and Jüppner H
- Subjects
- Adolescent, Child, Child, Preschool, Cohort Studies, DNA Methylation, Epigenesis, Genetic, Female, Humans, Infant, Male, Multiplex Polymerase Chain Reaction, Mutation, Pseudohypoparathyroidism, Chromogranins genetics, GTP-Binding Protein alpha Subunits, Gs genetics, Pediatric Obesity genetics, Pseudohypoparathyroidism genetics, Syntaxin 16 genetics
- Abstract
Context: Early-onset obesity, characteristic for disorders affecting the leptin-melanocortin pathway, is also observed in pseudohypoparathyroidism type 1A (PHP1A), a disorder caused by maternal GNAS mutations that disrupt expression or function of the stimulatory G protein α-subunit (Gsα). Mutations and/or epigenetic abnormalities at the same genetic locus are also the cause of pseudohypoparathyroidism type 1B (PHP1B). However, although equivalent biochemical and radiographic findings can be encountered in these related disorders caused by GNAS abnormalities, they are considered distinct clinical entities., Objectives: To further emphasize the overlapping features between both disorders, we report the cases of several children, initially brought to medical attention because of unexplained early-onset obesity, in whom PHP1B or PHP1A was eventually diagnosed., Patients and Methods: Search for GNAS methylation changes or mutations in cohorts of patients with early-onset obesity., Results: Severe obesity had been noted in five infants, with a later diagnosis of PHP1B due to STX16 deletions and/or abnormal GNAS methylation. These findings prompted analysis of 24 unselected obese patients, leading to the discovery of inherited STX16 deletions in 2 individuals. Similarly, impressive early weight gains were noted in five patients, who initially lacked additional Albright hereditary osteodystrophy features but in whom PHP1A due to GNAS mutations involving exons encoding Gsα was diagnosed., Conclusions: Obesity during the first year of life can be the first clinical evidence for PHP1B, expanding the spectrum of phenotypic overlap between PHP1A and PHP1B. Importantly, GNAS methylation abnormalities escape detection by targeted or genome-wide sequencing strategies, raising the question of whether epigenetic GNAS analyses should be considered for unexplained obesity., (Copyright © 2017 Endocrine Society)
- Published
- 2017
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37. Is one diagnosis the whole story? patients with double diagnoses.
- Author
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Kurolap A, Orenstein N, Kedar I, Weisz Hubshman M, Tiosano D, Mory A, Levi Z, Marom D, Cohen L, Ekhilevich N, Douglas J, Nowak CB, Tan WH, and Baris HN
- Subjects
- Adolescent, Adult, Aneuploidy, Child, Child, Preschool, Chromosome Deletion, Chromosome Duplication, Clinical Decision-Making, Female, Genetic Diseases, Inborn therapy, Genetic Testing, Genetic Variation, Humans, Infant, Infant, Newborn, Male, Middle Aged, Risk Factors, Young Adult, Genetic Association Studies, Genetic Diseases, Inborn diagnosis, Genetic Diseases, Inborn genetics
- Abstract
One of the goals of evaluating a patient in the genetics clinic is to find the diagnosis that would explain his or her clinical presentation. Sometimes the patient's diagnosis remains undefined or does not explain all of the clinical findings. As clinicians are often guided by a "single disorder" paradigm, diagnosing multiple genetic conditions in the same patient requires a heightened sense of awareness. Over the last few years, we evaluated several patients (n = 14) who were found to have more than one genetic diagnosis. In this paper, we will describe their natural history and diagnoses, and draw on the lessons learned from this phenomenon, which we expect to grow in this era of next-generation diagnostic technologies. To our knowledge, this is by far the largest series of patients with double diagnoses. Based on our findings, we strongly recommend that physicians question every diagnosis to determine whether it indeed explains all of the patients' symptoms, and consider whether they should continue the diagnostic evaluation to look for a more accurate and complete set of diagnoses. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
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38. Latitudinal Clines of the Human Vitamin D Receptor and Skin Color Genes.
- Author
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Tiosano D, Audi L, Climer S, Zhang W, Templeton AR, Fernández-Cancio M, Gershoni-Baruch R, Sánchez-Muro JM, El Kholy M, and Hochberg Z
- Subjects
- Adaptation, Biological genetics, Alleles, Computational Biology methods, Epistasis, Genetic, Gene Frequency, Gene Regulatory Networks, Genetic Linkage, Genome, Human, Genomics methods, Genotype, Humans, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Altitude, Gene-Environment Interaction, Receptors, Calcitriol genetics, Skin Pigmentation genetics
- Abstract
The well-documented latitudinal clines of genes affecting human skin color presumably arise from the need for protection from intense ultraviolet radiation (UVR) vs. the need to use UVR for vitamin D synthesis. Sampling 751 subjects from a broad range of latitudes and skin colors, we investigated possible multilocus correlated adaptation of skin color genes with the vitamin D receptor gene (VDR), using a vector correlation metric and network method called BlocBuster. We discovered two multilocus networks involving VDR promoter and skin color genes that display strong latitudinal clines as multilocus networks, even though many of their single gene components do not. Considered one by one, the VDR components of these networks show diverse patterns: no cline, a weak declining latitudinal cline outside of Africa, and a strong in- vs. out-of-Africa frequency pattern. We confirmed these results with independent data from HapMap. Standard linkage disequilibrium analyses did not detect these networks. We applied BlocBuster across the entire genome, showing that our networks are significant outliers for interchromosomal disequilibrium that overlap with environmental variation relevant to the genes' functions. These results suggest that these multilocus correlations most likely arose from a combination of parallel selective responses to a common environmental variable and coadaptation, given the known Mendelian epistasis among VDR and the skin color genes., (Copyright © 2016 Tiosano et al.)
- Published
- 2016
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39. Global Consensus Recommendations on Prevention and Management of Nutritional Rickets.
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Munns CF, Shaw N, Kiely M, Specker BL, Thacher TD, Ozono K, Michigami T, Tiosano D, Mughal MZ, Mäkitie O, Ramos-Abad L, Ward L, DiMeglio LA, Atapattu N, Cassinelli H, Braegger C, Pettifor JM, Seth A, Idris HW, Bhatia V, Fu J, Goldberg G, Sävendahl L, Khadgawat R, Pludowski P, Maddock J, Hyppönen E, Oduwole A, Frew E, Aguiar M, Tulchinsky T, Butler G, and Högler W
- Subjects
- Calcium deficiency, Child, Child, Preschool, Consensus, Health Policy, Humans, Infant, Mothers, Osteomalacia diagnosis, Osteomalacia therapy, Rickets therapy, Risk Factors, Vitamin D administration & dosage, Vitamin D therapeutic use, Vitamin D Deficiency therapy, Vitamins administration & dosage, Vitamins therapeutic use, Recommended Dietary Allowances, Rickets prevention & control
- Abstract
Background: Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication., Evidence: A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describe the strength of the recommendation and the quality of supporting evidence., Process: Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus., Results: This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts., Conclusion: Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required.
- Published
- 2016
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40. Evo-devo of Child Growth: The Role of Weaning in the Transition from Infancy to Childhood.
- Author
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Shaoul R, Tiosano D, and Hochberg Z
- Subjects
- Child, Humans, Infant, Child Development physiology, Child Nutritional Physiological Phenomena, Infant Nutritional Physiological Phenomena, Weaning
- Abstract
Homo sapiens are unique in having a life history phase of childhood, which follows infancy, as defined by breastfeeding. This review uses evolutionary life history theory in understanding child growth in a broad evolutionary perspective, using the data and theory of evolutionary predictive adaptive growth-related strategies for transition from infancy to childhood. We have previously shown that a delayed infancy-childhood transition has a lifelong impact on stature. Feeding practices during infancy are fundamental elements of nutrition as they program for future growth and body composition. A relationship between the duration of breastfeeding and the nature of weaning has been suggested as a possible cause for later obesity and growth patterns. This review highlights the role that breast milk feeding and variations in the weaning age have on transition to childhood, growth, and body composition.
- Published
- 2016
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41. Duodenal Expression of 25 Hydroxyvitamin D3-1α-hydroxylase Is Higher in Adolescents Than in Children and Adults.
- Author
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Gawlik A, Gepstein V, Rozen N, Dahan A, Ben-Yosef D, Wildbaum G, Verbitsky O, Shaoul R, Weisman Y, and Tiosano D
- Subjects
- 25-Hydroxyvitamin D3 1-alpha-Hydroxylase genetics, Adolescent, Adult, Age Factors, Aged, Animals, Child, Child, Preschool, Duodenum drug effects, Female, Humans, Insulin-Like Growth Factor I genetics, Insulin-Like Growth Factor I metabolism, Male, Mice, Middle Aged, Podophyllotoxin analogs & derivatives, Podophyllotoxin pharmacology, Receptor, IGF Type 1 antagonists & inhibitors, Sexual Maturation drug effects, Young Adult, 25-Hydroxyvitamin D3 1-alpha-Hydroxylase metabolism, Duodenum metabolism, Sexual Maturation physiology
- Abstract
Context: Puberty is associated with increased dietary calcium absorption. However, little is known about the metabolic adaptations that enhance calcium absorption during puberty., Objectives: To investigate duodenal 25-hydroxy vitamin D-1α-hydroxylase (CYP 27B1) mRNA expression and duodenal 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) production in children, adolescents, and adults., Design and Methods: CYP27B1a nd IGF1 mRNA expression and 1,25(OH)2D3 production were determined in duodenal biopsies. CYP27B1 expression was also determined after IGF1R inhibitor treatment of human and mice duodenal explants. mRNA expression was determined by RT-PCR, and CYP27B1 activity was determined by incubating duodenal explants with 25(OH)D3 and measuring 1,25(OH)2D3 production by radioimmunoassay., Results: CYP27B1 mRNA expression was 13.7 and 10.4 times higher in biopsies from adolescents compared to adults and children, respectively. IGF1 mRNA expression was 30% and 45% higher in explants from adolescents and children, respectively, compared to adults. Inhibition of IGF1 receptor activity decreased CYP27B1 expression in explants from both mice (85%) and humans (24%). 1,25(OH)2D3 production reached a maximum velocity of 768 ± 268 pmol/l/mg protein at 748.8 nmol/l of 25(OH)D3 in children and adolescents, whereas the maximum velocity was 86.4 ± 43.2 pmol/l/mg protein in adults. The substrate concentration at which the enzyme shows half of its maximum activity was similar in all groups, ranging between 624 and 837 nmol/L of 25(OH)D3., Conclusions: Increased CYP27B1 expression and local duodenal 1,25(OH)2D3 production during puberty may be a metabolic adaptation that promotes dietary calcium absorption. IGF1, a major factor in skeletal growth, is also involved in the modulation of CYP27B1 expression in the gut and may increase calcium supply for the growing bone.
- Published
- 2015
- Full Text
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42. Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations.
- Author
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Villanueva C, Jacobson-Dickman E, Xu C, Manouvrier S, Dwyer AA, Sykiotis GP, Beenken A, Liu Y, Tommiska J, Hu Y, Tiosano D, Gerard M, Leger J, Drouin-Garraud V, Lefebvre H, Polak M, Carel JC, Phan-Hug F, Hauschild M, Plummer L, Rey JP, Raivio T, Bouloux P, Sidis Y, Mohammadi M, de Roux N, and Pitteloud N
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Amino Acid Sequence, Animals, Conserved Sequence, Female, Genetic Association Studies, Humans, Hypogonadism metabolism, Limb Deformities, Congenital metabolism, MAP Kinase Signaling System, Male, Membrane Proteins metabolism, Molecular Sequence Data, Pedigree, Phosphorylation, Receptor, Fibroblast Growth Factor, Type 1 metabolism, Hypogonadism congenital, Hypogonadism genetics, Limb Deformities, Congenital genetics, Mutation, Receptor, Fibroblast Growth Factor, Type 1 genetics
- Abstract
Purpose: Congenital hypogonadotropic hypogonadism (CHH) and split hand/foot malformation (SHFM) are two rare genetic conditions. Here we report a clinical entity comprising the two., Methods: We identified patients with CHH and SHFM through international collaboration. Probands and available family members underwent phenotyping and screening for FGFR1 mutations. The impact of identified mutations was assessed by sequence- and structure-based predictions and/or functional assays., Results: We identified eight probands with CHH with (n = 3; Kallmann syndrome) or without anosmia (n = 5) and SHFM, seven of whom (88%) harbor FGFR1 mutations. Of these seven, one individual is homozygous for p.V429E and six individuals are heterozygous for p.G348R, p.G485R, p.Q594*, p.E670A, p.V688L, or p.L712P. All mutations were predicted by in silico analysis to cause loss of function. Probands with FGFR1 mutations have severe gonadotropin-releasing hormone deficiency (absent puberty and/or cryptorchidism and/or micropenis). SHFM in both hands and feet was observed only in the patient with the homozygous p.V429E mutation; V429 maps to the fibroblast growth factor receptor substrate 2α binding domain of FGFR1, and functional studies of the p.V429E mutation demonstrated that it decreased recruitment and phosphorylation of fibroblast growth factor receptor substrate 2α to FGFR1, thereby resulting in reduced mitogen-activated protein kinase signaling., Conclusion: FGFR1 should be prioritized for genetic testing in patients with CHH and SHFM because the likelihood of a mutation increases from 10% in the general CHH population to 88% in these patients.
- Published
- 2015
- Full Text
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43. The beneficial effect of growth hormone treatment on islet mass in streptozotocin-treated mice.
- Author
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Scheinman EJ, Damouni R, Caspi A, Shen-Orr Z, Tiosano D, and LeRoith D
- Subjects
- Animals, Diabetes Mellitus, Experimental pathology, Female, Islets of Langerhans pathology, Mice, Mice, Inbred C57BL, Organ Size, Recombinant Proteins, Diabetes Mellitus, Experimental blood, Human Growth Hormone pharmacology, Insulin blood, Islets of Langerhans drug effects
- Abstract
Background: Type 1 diabetes is an autoimmune disease, characterized by a loss of pancreatic β-cell mass and function, which results in dramatic reductions in insulin secretion and circulating insulin levels. Patients with type 1 diabetes are traditionally treated with insulin injections and insulin pumps ex vivo or undergo transplantation. Growth hormone (GH) has been shown to be involved in β-cell function and survival in culture., Methods: Twelve-week-old female C57BL/6 mice were treated with streptozotocin and monitored for their weight and blood glucose levels. Fourteen days post-initial injection, these mice were separated into two groups at random. One group was treated with GH while the other treated with vehicle for up to 3 weeks. These mice were compared with mice not treated with streptozotocin., Results: Under our experimental conditions, we observed that mice treated with GH had larger islets and higher serum insulin levels than streptozotocin-treated mice treated with saline (0.288 vs. 0.073 ng/mL, p < 0.01)., Conclusions: Our data demonstrate that GH may rescue islets and therefore may possess therapeutic potential in the treatment of type 1 diabetes, although consideration should be made regarding GH's effect on insulin resistance., (Copyright © 2014 John Wiley & Sons, Ltd.)
- Published
- 2015
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44. TSH elevations as the first laboratory evidence for pseudohypoparathyroidism type Ib (PHP-Ib).
- Author
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Molinaro A, Tiosano D, Takatani R, Chrysis D, Russell W, Koscielniak N, Kottler ML, Agretti P, De Marco G, Ahtiainen P, Christov M, Mäkitie O, Tonacchera M, and Jüppner H
- Subjects
- Adult, Child, Preschool, Chromosomes, Human, Pair 20 genetics, Epigenesis, Genetic, Exons genetics, Female, Humans, Infant, Infant, Newborn, Male, Pseudohypoparathyroidism genetics, Syntaxin 16 genetics, Young Adult, Pseudohypoparathyroidism, Pseudohypoparathyroidism blood, Thyrotropin blood
- Abstract
Hypocalcemia and hyperphosphatemia because of resistance toward parathyroid hormone (PTH) in the proximal renal tubules are the most prominent abnormalities in patients affected by pseudohypoparathyroidism type Ib (PHP-Ib). In this rare disorder, which is caused by GNAS methylation changes, resistance can occur toward other hormones, such as thyroid-stimulating hormone (TSH), that mediate their actions through G protein-coupled receptors. However, these additional laboratory abnormalities are usually not recognized until PTH-resistant hypocalcemia becomes clinically apparent. We now describe four pediatric patients, first diagnosed with subclinical or overt hypothyroidism between the ages of 0.2 and 15 years, who developed overt PTH-resistance 3 to 20 years later. Although anti-thyroperoxidase (anti-TPO) antibodies provided a plausible explanation for hypothyroidism in one of these patients, this and two other patients revealed broad epigenetic GNAS abnormalities, which included loss of methylation (LOM) at exons AS, XL, and A/B, and gain of methylation at exon NESP55; ie, findings consistent with PHP-Ib. LOM at GNAS exon A/B alone led in the fourth patient to the identification of a maternally inherited 3-kb STX16 deletion, a well-established cause of autosomal dominant PHP-Ib. Although GNAS methylation changes were not detected in additional pediatric and adult patients with subclinical hypothyroidism (23 pediatric and 39 adult cases), hypothyroidism can obviously be the initial finding in PHP-Ib patients. One should therefore consider measuring PTH, along with calcium and phosphate, in patients with unexplained hypothyroidism for extended periods of time to avoid hypocalcemia and associated clinical complications., (© 2014 American Society for Bone and Mineral Research.)
- Published
- 2015
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45. Evidence of ERalpha and ERbeta selectivity and partial estrogen agonism in traditional Chinese medicine.
- Author
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Tiosano D, Paris F, Grimaldi M, Georgescu V, Servant N, Hochberg Z, Balaguer P, and Sultan C
- Subjects
- Child, Preschool, Drug Partial Agonism, Drugs, Chinese Herbal pharmacology, Estrogen Receptor alpha genetics, Estrogen Receptor alpha metabolism, Estrogen Receptor beta genetics, Estrogen Receptor beta metabolism, Genes, Reporter drug effects, Growth Disorders metabolism, Growth Disorders pathology, Humans, MCF-7 Cells, Male, Osteogenesis drug effects, Phytoestrogens pharmacology, Treatment Outcome, Drugs, Chinese Herbal therapeutic use, Estrogen Receptor alpha agonists, Estrogen Receptor beta agonists, Growth Disorders drug therapy, Phytoestrogens therapeutic use
- Abstract
The use of complementary and alternative medicine and herbal products, especially traditional Chinese medicines, is progressively rising for both adults and children. This increased use is based on the popular belief that these medicines are safe and harmless. In this report, we describe the results of a bedside-to-bench study that involved a short-statured 4-year-old boy with deficiencies in growth hormone, thyroid stimulating hormone, and adrenocorticotropic hormone due to an ectopic posterior pituitary gland and invisible pituitary stalk. Although the boy was given replacement therapy with hydrocortisone and L-thyroxin, the parents refused to treat him with growth hormone and consulted a naturopath who prescribed a traditional Chinese medicine (TCM) to stimulate the boy's growth. From the age of 20 months, the child's growth was regularly monitored while he was being treated with hydrocortisone, thyroxin, and the TCM. Over a 36-month period, the child's growth velocity accelerated (3 cm/year to 8 cm/year), his height increment substantially increased (-2 SD to -0.8 SD), and his bones matured. In the laboratory investigation, estrogen receptor (ER)alpha and ERbeta reporter cell lines were used to characterize the estrogenic activity of the TCM medicine and its 18 components, and the results established that the medicine and some of its components have estrogen receptor ERalpha and ERbeta selectivity and partial estrogen agonism. Partial estrogenic activity of the TCM was confirmed using whole-cell competitive binding, cell proliferation, and endogenous gene expression assays in the ERalpha-positive breast cancer cell lines. Although the presence of evidence is not always evidence of causality, we have concluded that this traditional Chinese medicine contains ingredients with estrogenic activity that can sustain bone growth and maturation without affecting other estrogen-dependent tissues.
- Published
- 2014
- Full Text
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46. Mutations in SLC34A3/NPT2c are associated with kidney stones and nephrocalcinosis.
- Author
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Dasgupta D, Wee MJ, Reyes M, Li Y, Simm PJ, Sharma A, Schlingmann KP, Janner M, Biggin A, Lazier J, Gessner M, Chrysis D, Tuchman S, Baluarte HJ, Levine MA, Tiosano D, Insogna K, Hanley DA, Carpenter TO, Ichikawa S, Hoppe B, Konrad M, Sävendahl L, Munns CF, Lee H, Jüppner H, and Bergwitz C
- Subjects
- Adult, Child, Child, Preschool, Female, Humans, Infant, Male, Mutation, Missense, Kidney Calculi genetics, Nephrocalcinosis genetics, Sodium-Phosphate Cotransporter Proteins, Type IIc genetics
- Abstract
Compound heterozygous and homozygous (comp/hom) mutations in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium (Na(+))-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a disorder characterized by renal phosphate wasting resulting in hypophosphatemia, correspondingly elevated 1,25(OH)2 vitamin D levels, hypercalciuria, and rickets/osteomalacia. Similar, albeit less severe, biochemical changes are observed in heterozygous (het) carriers and indistinguishable from those changes encountered in idiopathic hypercalciuria (IH). Here, we report a review of clinical and laboratory records of 133 individuals from 27 kindreds, including 5 previously unreported HHRH kindreds and two cases with IH, in which known and novel SLC34A3 mutations (c.1357delTTC [p.F453del]; c.G1369A [p.G457S]; c.367delC) were identified. Individuals with mutations affecting both SLC34A3 alleles had a significantly increased risk of kidney stone formation or medullary nephrocalcinosis, namely 46% compared with 6% observed in healthy family members carrying only the wild-type SLC34A3 allele (P=0.005) or 5.64% in the general population (P<0.001). Renal calcifications were also more frequent in het carriers (16%; P=0.003 compared with the general population) and were more likely to occur in comp/hom and het individuals with decreased serum phosphate (odds ratio [OR], 0.75, 95% confidence interval [95% CI], 0.59 to 0.96; P=0.02), decreased tubular reabsorption of phosphate (OR, 0.41; 95% CI, 0.23 to 0.72; P=0.002), and increased serum 1,25(OH)2 vitamin D (OR, 1.22; 95% CI, 1.05 to 1.41; P=0.008). Additional studies are needed to determine whether these biochemical parameters are independent of genotype and can guide therapy to prevent nephrocalcinosis, nephrolithiasis, and potentially, CKD., (Copyright © 2014 by the American Society of Nephrology.)
- Published
- 2014
- Full Text
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47. A mutated vitamin D receptor in hereditary vitamin D-resistant rickets prevents induction of bronchial hyperreactivity and inflammation.
- Author
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Bar-Yoseph R, Bentur L, Goldbart A, Livnat G, Hakim F, Weisman Y, and Tiosano D
- Subjects
- Adolescent, Adult, Asthma immunology, Asthma physiopathology, Biomarkers, Breath Tests, Bronchial Hyperreactivity diagnosis, Bronchial Hyperreactivity immunology, Child, Cytokines blood, Familial Hypophosphatemic Rickets immunology, Female, Humans, Male, Mutation, Pneumonia diagnosis, Pneumonia immunology, Receptors, Calcitriol immunology, Skin Tests, Spirometry, Vitamin D analogs & derivatives, Vitamin D blood, Young Adult, Asthma genetics, Bronchial Hyperreactivity genetics, Familial Hypophosphatemic Rickets genetics, Pneumonia genetics, Receptors, Calcitriol genetics
- Abstract
Context: Previous studies have reported an association between vitamin D deficiency and asthma. Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) patients provide a natural model to assess the role of the vitamin D receptor (VDR) in regulating human lung immune responses and airway hyperreactivity., Objectives: The aim of the study was to determine the role of the VDR on lung functions, airways, and systemic markers of inflammation and allergy in HVDRR patients., Design and Methods: Thirteen HVDRR patients (aged 6-37 y) and 17 normal controls (aged 6-38 y) underwent spirometry, a methacholine challenge test (MCT), blood tests, allergy skin tests, determination of fractional exhaled nitric oxide, and measurement of serum and exhaled breath condensate cytokines, including IL-4, IL-5, IL-10, IL-17, and interferon-γ levels., Results: All HVDRR patients had negative MCT results, whereas six controls (35.3%) had positive MCT results (P < .014). Serum IgE levels, eosinophil counts, and fractional exhaled nitric oxide and allergy skin test results were similar for the HVDRR patients and controls, as were the serum cytokine concentrations. The HVDRR patients had different cytokine levels in their exhaled breath condensate (increased IL-4 and IL-17 and decreased IL-5, IL-10, and interferon-γ levels) compared to the controls (P < .005)., Conclusions: HVDRR patients show diverse exhaled cytokine profiles but seem to be protected against provoked bronchial hyperreactivity and clinical asthma. These findings suggest that an intact VDR has an important role in asthma pathophysiology.
- Published
- 2014
- Full Text
- View/download PDF
48. Update on vitamin D during childhood.
- Author
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Abrams SA and Tiosano D
- Subjects
- Bone Density, Child, Child Nutritional Physiological Phenomena, Child, Preschool, Dietary Supplements, Female, Humans, Hypercalcemia drug therapy, Hypercalcemia metabolism, Hypersensitivity drug therapy, Hypersensitivity metabolism, Infant, Lung Diseases drug therapy, Lung Diseases metabolism, Rickets drug therapy, Rickets metabolism, Vitamin D Deficiency drug therapy, Vitamin D Deficiency metabolism, Calcium, Dietary metabolism, Hypercalcemia etiology, Hypersensitivity etiology, Lung Diseases etiology, Rickets etiology, Vitamin D Deficiency complications
- Abstract
Purpose of Review: We propose to review several recent key clinically oriented topics related to vitamin D and health in children., Recent Findings: We found a very large number of recent clinical studies related to vitamin D. However, most are association studies with few physiological or clinical trials that are adequately powered for clinical outcomes. Key results are available related to pulmonary disease and allergic disorders. Recent studies have also evaluated the relationship of vitamin D to bone health as well as new insights into genetic conditions related to vitamin D metabolism., Summary: Recent studies generally support the recommendations of the Institute of Medicine related to vitamin D intake but there is new and increasing evidence that some health conditions, such as pulmonary diseases in children, might benefit from close monitoring of vitamin D status. However, controlled trials are mostly lacking and there is an inadequate basis from recent studies to recommend high dose vitamin D pending the results of controlled trials.
- Published
- 2014
- Full Text
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49. Postzygotic HRAS mutation causing both keratinocytic epidermal nevus and thymoma and associated with bone dysplasia and hypophosphatemia due to elevated FGF23.
- Author
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Avitan-Hersh E, Tatur S, Indelman M, Gepstein V, Shreter R, Hershkovitz D, Brick R, Bergman R, and Tiosano D
- Subjects
- Adolescent, Bone Diseases, Developmental blood, Bone Diseases, Developmental genetics, Fibroblast Growth Factor-23, Humans, Hypophosphatemia blood, Hypophosphatemia genetics, Keratinocytes pathology, Male, Mutation physiology, Nevus, Nevus, Pigmented complications, Nevus, Pigmented pathology, Skin Neoplasms complications, Skin Neoplasms pathology, Thymoma complications, Thymus Neoplasms complications, Up-Regulation, Zygote metabolism, Bone Diseases, Developmental complications, Fibroblast Growth Factors blood, Genes, ras physiology, Hypophosphatemia complications, Nevus, Pigmented genetics, Skin Neoplasms genetics, Thymoma genetics, Thymus Neoplasms genetics
- Abstract
Introduction: Epidermal nevus syndrome is a rare group of disorders characterized by the combination of congenital epidermal nevi and extracutaneous features, including skeletal, neurological, ocular, and other systemic findings. We report a case of keratinocytic epidermal nevus syndrome that includes a thymoma, bone dysplasia, and hypophosphatemia with elevated fibroblast growth factor 23 (FGF23) levels associated with postzygotic HRAS mutation., Case Report: A 14-year-old boy was admitted due to recent limping. The physical examination revealed multiple right-sided linear epidermal nevi along Blaschko's lines. Magnetic resonance imaging showed cystic lesions in cervical bones and thymoma, and x-ray examination showed cystic lesions in the hands. Biochemical studies demonstrated severe hypophosphatemia, normocalcemia, high normal PTH, low 25-hydroxyvitamin D and low 1,25-dihydroxyvitamin D levels. The serum FGF23 C-terminal level was normal, but the intact FGF23 level was found to be elevated. Genetic evaluation revealed a heterozygote mutation in the HRAS gene in both the keratinocytic epidermal nevus and thymoma but not in DNA extracted from blood lymphocytes, thus establishing the mutation as postzygotic., Discussion: Postzygotic mutations in HRAS lead to elevation of FGF23 levels, as found in mutated PHEX, FGF23, DMP1, and ENPP1 genes, which lead to hypophosphatemia., Conclusion: An identical postzygotic HRAS mutation was shown to be present in both keratinocytic epidermal nevus and thymoma and to be associated with bone lesions and hypophosphatemia due to elevated FGF23 levels. These may all be related to the HRAS mutation.
- Published
- 2014
- Full Text
- View/download PDF
50. The role of vitamin D receptor in innate and adaptive immunity: a study in hereditary vitamin D-resistant rickets patients.
- Author
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Tiosano D, Wildbaum G, Gepstein V, Verbitsky O, Weisman Y, Karin N, and Eztioni A
- Subjects
- Adolescent, Adult, Case-Control Studies, Cells, Cultured, Child, Child, Preschool, Familial Hypophosphatemic Rickets blood, Familial Hypophosphatemic Rickets pathology, Female, Gene Expression Regulation immunology, Humans, Lymphocytes immunology, Lymphocytes metabolism, Lymphocytes physiology, Male, Monocytes immunology, Monocytes metabolism, Monocytes physiology, Receptors, Calcitriol genetics, Receptors, Calcitriol metabolism, Young Adult, Adaptive Immunity genetics, Familial Hypophosphatemic Rickets genetics, Immunity, Innate genetics, Receptors, Calcitriol physiology
- Abstract
Context: Vitamin D has regulatory effects on innate and adaptive immunity. Curiously, hereditary vitamin D-resistant rickets (HVDRR) patients show no increased incidence of infectious or autoimmune diseases., Objectives: The aim of the study was to investigate the role of vitamin D and the vitamin D receptor (VDR) in innate and adaptive immune responses in monocytes and lymphocytes from HVDRR patients., Design and Methods: Fifteen HVDRR patients and 17 controls participated in the investigation. Activated monocytes (lipopolysaccharides) and lymphocytes (anti-CD3, CD28, and α-GalCer) were incubated with and without 25(OH)D3 (100 nM). The mRNA expressions of CYP27B1 and VDR; vitamin D response (TLR2); vitamin D response elements binding protein (hnRNP); antimicrobial peptides cathelicidin and β-defensin; the transcription factor enhancer binding proteins C/EBPα, C/EBPβ, and C/EBPε and enzymes involved in NO generation, Nos2, and Arginase1 were analyzed by RT-PCR. TNF-α, interferon-γ, IL-4, IL-10, and IL-17 concentrations in lymphocyte cultures media were measured by ELISA., Results: Cathelicidin expression was lower in HVDRR monocytes than in control monocytes. 25(OH)D3 increased significantly the expression of cathelicidin in control monocytes (2.3-fold) but only slightly in HVDRR monocytes. 25(OH)D3 increased the expression of VDR (2-fold), C/EBPε (2-fold), C/EBPβ (1.7-fold), and hnRNP and suppressed TLR2 only in control monocytes. Unexpectedly, 25(OH)D3 increased the expression of CYP27b1, C/EBPα, Nos2, and Arginase1 in HVDRR monocytes. TNFα and IL-17 concentrations were significantly higher in HVDRR lymphocyte cultures than in controls. 25(OH)D3 suppressed IL-17 only in control lymphocyte. 25(OH)D3 increased IL-4, IL-10, and interferon-γ concentrations in control lymphocyte media but not in HVDRR., Conclusions: Our results demonstrate impairments in various components of innate immunity in HVDTRR patients' monocytes and a proinflammatory cytokine profile in their lymphocytes. The underlying VDR-independent compensatory mechanisms that protect HVDRR patients from infections and autoimmune diseases remain undetermined.
- Published
- 2013
- Full Text
- View/download PDF
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