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3. Variants in Mitochondrial ATP Synthase Cause Variable Neurologic Phenotypes

Author

Zech, M., Kopajtich, R., Steinbrücker, K., Bris, C., Gueguen, N., Feichtinger, R.G., Achleitner, M.T., Duzkale, N., Périvier, M., Koch, J., Engelhardt, H., Freisinger, P., Wagner, M., Brunet, T., Berutti, R., Smirnov, D., Navaratnarajah, T., Rodenburg, R.J.T., Pais, L.S., Austin-Tse, C., O'Leary, M., Boesch, S., Jech, R., Bakhtiari, S., Jin, S.C., Wilbert, F., Kruer, M.C., Wortmann, S.B., Eckenweiler, M., Mayr, J.A., Distelmaier, F., Steinfeld, R., Winkelmann, J., Prokisch, H., Zech, M., Kopajtich, R., Steinbrücker, K., Bris, C., Gueguen, N., Feichtinger, R.G., Achleitner, M.T., Duzkale, N., Périvier, M., Koch, J., Engelhardt, H., Freisinger, P., Wagner, M., Brunet, T., Berutti, R., Smirnov, D., Navaratnarajah, T., Rodenburg, R.J.T., Pais, L.S., Austin-Tse, C., O'Leary, M., Boesch, S., Jech, R., Bakhtiari, S., Jin, S.C., Wilbert, F., Kruer, M.C., Wortmann, S.B., Eckenweiler, M., Mayr, J.A., Distelmaier, F., Steinfeld, R., Winkelmann, J., and Prokisch, H.

Abstract

Item does not contain fulltext, OBJECTIVE: ATP synthase (ATPase) is responsible for the majority of ATP production. Nevertheless, disease phenotypes associated with mutations in ATPase subunits are extremely rare. We aimed at expanding the spectrum of ATPase-related diseases. METHODS: Whole-exome sequencing in cohorts with 2,962 patients diagnosed with mitochondrial disease and/or dystonia and international collaboration were used to identify deleterious variants in ATPase-encoding genes. Findings were complemented by transcriptional and proteomic profiling of patient fibroblasts. ATPase integrity and activity were assayed using cells and tissues from 5 patients. RESULTS: We present 10 total individuals with biallelic or de novo monoallelic variants in nuclear ATPase subunit genes. Three unrelated patients showed the same homozygous missense ATP5F1E mutation (including one published case). An intronic splice-disrupting alteration in compound heterozygosity with a nonsense variant in ATP5PO was found in one patient. Three patients had de novo heterozygous missense variants in ATP5F1A, whereas another 3 were heterozygous for ATP5MC3 de novo missense changes. Bioinformatics methods and populational data supported the variants' pathogenicity. Immunohistochemistry, proteomics, and/or immunoblotting revealed significantly reduced ATPase amounts in association to ATP5F1E and ATP5PO mutations. Diminished activity and/or defective assembly of ATPase was demonstrated by enzymatic assays and/or immunoblotting in patient samples bearing ATP5F1A-p.Arg207His, ATP5MC3-p.Gly79Val, and ATP5MC3-p.Asn106Lys. The associated clinical profiles were heterogeneous, ranging from hypotonia with spontaneous resolution (1/10) to epilepsy with early death (1/10) or variable persistent abnormalities, including movement disorders, developmental delay, intellectual disability, hyperlactatemia, and other neurologic and systemic features. Although potentially reflecting an ascertainment bias, dystonia was common (7/10). INTERPRETA

Published
2022

4. Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia

Author

Wiessner, M., Maroofian, R., Ni, M.Y., Pedroni, A., Müller, J.S., Stucka, R., Beetz, C., Efthymiou, S., Santorelli, F.M., Alfares, A.A., Zhu, C., Meszarosova, A. Uhrova, Alehabib, E., Bakhtiari, S., Janecke, A.R., Otero, M.G., Chen, J.Y., Peterson, J.T., Strom, T.M., Jonghe, P. De, Deconinck, T., Ridder, W. De, Winter, J., Pasquariello, R., Ricca, I., Alfadhel, M., Warrenburg, B.P.C. van de, Portier, R., Bergmann, C., Firouzabadi, S. Ghasemi, Jin, S.C., Bilguvar, K., Hamed, S., Abdelhameed, M., Haridy, N.A., Maqbool, S., Rahman, F., Anwar, N., Carmichael, J., Pagnamenta, A., Wood, N.W., Mau-Them, F. Tran, Haack, T., Rocco, M. Di, Ceccherini, I., Iacomino, M., Zara, F., Salpietro, V., Scala, M., Rusmini, M., Xu, Y., Wang, Y., Suzuki, Y., Koh, K., Nan, H., Ishiura, H., Tsuji, S., Lambert, L., Schmitt, E., Lacaze, E., Küpper, H., Dredge, D., Skraban, C., Goldstein, A., Willis, M.J.H., Grand, K., Graham, J.M., Lewis, R.A., Millan, F., Duman, Ö., Dündar, N., Uyanik, G., Schöls, L., Nürnberg, P., Nürnberg, G., Bordes, A. Catala, Seeman, P., Kuchar, M., Darvish, H., Rebelo, A., Bouçanova, F., Medard, J.J., Chrast, R., Auer-Grumbach, M., Alkuraya, F.S., Shamseldin, H., Tala, S. Al, Varaghchi, J. Rezazadeh, Najafi, Maryam, Deschner, S., Gläser, D., Hüttel, W., Kruer, M.C., Kamsteeg, E.J., Takiyama, Y., Züchner, S., Baets, J., Synofzik, M., Schüle, R., Horvath, R., Pierson, T.M., Senderek, J., Wiessner, M., Maroofian, R., Ni, M.Y., Pedroni, A., Müller, J.S., Stucka, R., Beetz, C., Efthymiou, S., Santorelli, F.M., Alfares, A.A., Zhu, C., Meszarosova, A. Uhrova, Alehabib, E., Bakhtiari, S., Janecke, A.R., Otero, M.G., Chen, J.Y., Peterson, J.T., Strom, T.M., Jonghe, P. De, Deconinck, T., Ridder, W. De, Winter, J., Pasquariello, R., Ricca, I., Alfadhel, M., Warrenburg, B.P.C. van de, Portier, R., Bergmann, C., Firouzabadi, S. Ghasemi, Jin, S.C., Bilguvar, K., Hamed, S., Abdelhameed, M., Haridy, N.A., Maqbool, S., Rahman, F., Anwar, N., Carmichael, J., Pagnamenta, A., Wood, N.W., Mau-Them, F. Tran, Haack, T., Rocco, M. Di, Ceccherini, I., Iacomino, M., Zara, F., Salpietro, V., Scala, M., Rusmini, M., Xu, Y., Wang, Y., Suzuki, Y., Koh, K., Nan, H., Ishiura, H., Tsuji, S., Lambert, L., Schmitt, E., Lacaze, E., Küpper, H., Dredge, D., Skraban, C., Goldstein, A., Willis, M.J.H., Grand, K., Graham, J.M., Lewis, R.A., Millan, F., Duman, Ö., Dündar, N., Uyanik, G., Schöls, L., Nürnberg, P., Nürnberg, G., Bordes, A. Catala, Seeman, P., Kuchar, M., Darvish, H., Rebelo, A., Bouçanova, F., Medard, J.J., Chrast, R., Auer-Grumbach, M., Alkuraya, F.S., Shamseldin, H., Tala, S. Al, Varaghchi, J. Rezazadeh, Najafi, Maryam, Deschner, S., Gläser, D., Hüttel, W., Kruer, M.C., Kamsteeg, E.J., Takiyama, Y., Züchner, S., Baets, J., Synofzik, M., Schüle, R., Horvath, R., Pierson, T.M., and Senderek, J.

Abstract

Item does not contain fulltext, Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.

Published
2021

5. Loss of TNR causes a nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus

Author

Wagner, M., Levy, J., Jung-Klawitter, S., Bakhtiari, S., Monteiro, F., Maroofian, R., Bierhals, T., Hempel, M., Elmaleh-Berges, M., Kitajima, J.P., Kim, C.A., Salomao, J.G., Amor, D.J., Cooper, M.S., Perrin, L., Pipiras, E., Neu, A., Doosti, M., Karimiani, E.G., Toosi, M.B., Houlden, H., Jin, S.C., Si, Y.C., Rodan, L.H., Venselaar, H., Kruer, M.C., Kok, F., Hoffmann, G.F., Strom, T.M., Wortmann, S.B., Tabet, A.C., Opladen, T., Wagner, M., Levy, J., Jung-Klawitter, S., Bakhtiari, S., Monteiro, F., Maroofian, R., Bierhals, T., Hempel, M., Elmaleh-Berges, M., Kitajima, J.P., Kim, C.A., Salomao, J.G., Amor, D.J., Cooper, M.S., Perrin, L., Pipiras, E., Neu, A., Doosti, M., Karimiani, E.G., Toosi, M.B., Houlden, H., Jin, S.C., Si, Y.C., Rodan, L.H., Venselaar, H., Kruer, M.C., Kok, F., Hoffmann, G.F., Strom, T.M., Wortmann, S.B., Tabet, A.C., and Opladen, T.

Abstract

Contains fulltext : 220941.pdf (Publisher’s version ) (Closed access), PURPOSE: TNR, encoding Tenascin-R, is an extracellular matrix glycoprotein involved in neurite outgrowth and neural cell adhesion, proliferation and migration, axonal guidance, myelination, and synaptic plasticity. Tenascin-R is exclusively expressed in the central nervous system with highest expression after birth. The protein is crucial in the formation of perineuronal nets that ensheath interneurons. However, the role of Tenascin-R in human pathology is largely unknown. We aimed to establish TNR as a human disease gene and unravel the associated clinical spectrum. METHODS: Exome sequencing and an online matchmaking tool were used to identify patients with biallelic variants in TNR. RESULTS: We identified 13 individuals from 8 unrelated families with biallelic variants in TNR sharing a phenotype consisting of spastic para- or tetraparesis, axial muscular hypotonia, developmental delay, and transient opisthotonus. Four homozygous loss-of-function and four different missense variants were identified. CONCLUSION: We establish TNR as a disease gene for an autosomal recessive nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus and highlight the role of central nervous system extracellular matrix proteins in the pathogenicity of spastic disorders.

Published
2020

6. De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

Author

Helbig, K.L., Lauerer, R.J., Bahr, J.C., Souza, I.A., Myers, C.T., Uysal, B., Schwarz, N., Gandini, M.A., Huang, S., Keren, B., Mignot, C., Afenjar, A., Villemeur, T. Billette de, Heron, D., Nava, C., Valence, S., Buratti, J., Fagerberg, C.R., Soerensen, K.P., Kibaek, M., Kamsteeg, E.J., Koolen, D.A., Gunning, B., Schelhaas, H.J., Kruer, M.C., Fox, J., Bakhtiari, S., Jarrar, R., Padilla-Lopez, S., Lindstrom, K., Jin, S.C., Zeng, X., Bilguvar, K., Papavasileiou, A., Xin, Q., Zhu, C., Boysen, K., Vairo, F., Lanpher, B.C., Klee, E.W., Tillema, J.M., Payne, E.T., Cousin, M.A., Kruisselbrink, T.M., Wick, M.J., Baker, J., Haan, E., Smith, N., Corbett, M.A., MacLennan, A.H., Gecz, J., Biskup, S., Goldmann, E., Rodan, L.H., Kichula, E., Segal, E., Jackson, K.E., Asamoah, A., Dimmock, D., McCarrier, J., Botto, L.D., Filloux, F., Tvrdik, T., Cascino, G.D., Klingerman, S., Neumann, C., Wang, R., Jacobsen, J.C., Nolan, M.A., Snell, R.G., Lehnert, K., Sadleir, L.G., Anderlid, B.M., Kvarnung, M., Guerrini, R., Friez, M.J., Lyons, M.J., Leonhard, J., Kringlen, G., Casas, K., Achkar, C.M. El, Smith, L.A., Rotenberg, A., Poduri, A., Sanchis-Juan, A., Carss, K.J., Rankin, J., Zeman, A., Raymond, F.L., Blyth, M., Kerr, B., Ruiz, K., Urquhart, J., Hughes, I., Banka, S., Hedrich, U.B.S., Scheffer, I.E., Helbig, I., Zamponi, G.W., Lerche, H., et al., Helbig, K.L., Lauerer, R.J., Bahr, J.C., Souza, I.A., Myers, C.T., Uysal, B., Schwarz, N., Gandini, M.A., Huang, S., Keren, B., Mignot, C., Afenjar, A., Villemeur, T. Billette de, Heron, D., Nava, C., Valence, S., Buratti, J., Fagerberg, C.R., Soerensen, K.P., Kibaek, M., Kamsteeg, E.J., Koolen, D.A., Gunning, B., Schelhaas, H.J., Kruer, M.C., Fox, J., Bakhtiari, S., Jarrar, R., Padilla-Lopez, S., Lindstrom, K., Jin, S.C., Zeng, X., Bilguvar, K., Papavasileiou, A., Xin, Q., Zhu, C., Boysen, K., Vairo, F., Lanpher, B.C., Klee, E.W., Tillema, J.M., Payne, E.T., Cousin, M.A., Kruisselbrink, T.M., Wick, M.J., Baker, J., Haan, E., Smith, N., Corbett, M.A., MacLennan, A.H., Gecz, J., Biskup, S., Goldmann, E., Rodan, L.H., Kichula, E., Segal, E., Jackson, K.E., Asamoah, A., Dimmock, D., McCarrier, J., Botto, L.D., Filloux, F., Tvrdik, T., Cascino, G.D., Klingerman, S., Neumann, C., Wang, R., Jacobsen, J.C., Nolan, M.A., Snell, R.G., Lehnert, K., Sadleir, L.G., Anderlid, B.M., Kvarnung, M., Guerrini, R., Friez, M.J., Lyons, M.J., Leonhard, J., Kringlen, G., Casas, K., Achkar, C.M. El, Smith, L.A., Rotenberg, A., Poduri, A., Sanchis-Juan, A., Carss, K.J., Rankin, J., Zeman, A., Raymond, F.L., Blyth, M., Kerr, B., Ruiz, K., Urquhart, J., Hughes, I., Banka, S., Hedrich, U.B.S., Scheffer, I.E., Helbig, I., Zamponi, G.W., and Lerche, H., et al.

Abstract

Item does not contain fulltext, Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the alpha1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.

Published
2018

7. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease

Author

Huang, K.-L. (Kuan-Lin), Marcora, E. (Edoardo), Pimenova, A.A. (Anna A.), Di Narzo, A.F. (Antonio F.), Kapoor, M. (Manav), Jin, S.C. (Sheng Chih), Harari, O. (Oscar), Bertelsen, S., Fairfax, B.P. (Benjamin), Czajkowski, J. (Jake), Chouraki, V. (Vincent), Grenier-Boley, B. (Benjamin), Bellenguez, C. (Céline), Deming, Y. (Yuetiva), McKenzie, A. (Andrew), Raj, T. (Towfique), Renton, A. (Alan), Budde, J. (John), Smith, A.V. (Albert), Fitzpatrick, A. (Annette), Bis, J.C. (Joshua), DeStefano, A.L. (Anita), Adams, H.H.H. (Hieab), Ikram, M.A. (Arfan), Lee, S.J. (Sven) van der, Del-Aguila, J.L. (Jorge L.), Fernandez, M.V. (Maria Victoria), Ibañez, L. (Laura), Sims, R. (Rebecca), Escott-Price, V. (Valentina), Mayeux, R. (Richard), Haines, J.L. (Jonathan), Farrer, L.A. (Lindsay), Pericak-Vance, M.A. (Margaret), Lambert, J.-C. (J.), Duijn, C.M. (Cornelia) van, Launer, L.J. (Lenore), Seshadri, S. (Sudha), Williams, J. (Julie), Amouyel, P. (Philippe), Schellenberg, G.D. (Gerard), Zhang, B. (Bin), Borecki, I.B. (Ingrid), Kauwe, J.S.K. (John S.K.), Cruchaga, C. (Carlos), Hao, K. (Ke), Goate, A.M. (Alison), Huang, K.-L. (Kuan-Lin), Marcora, E. (Edoardo), Pimenova, A.A. (Anna A.), Di Narzo, A.F. (Antonio F.), Kapoor, M. (Manav), Jin, S.C. (Sheng Chih), Harari, O. (Oscar), Bertelsen, S., Fairfax, B.P. (Benjamin), Czajkowski, J. (Jake), Chouraki, V. (Vincent), Grenier-Boley, B. (Benjamin), Bellenguez, C. (Céline), Deming, Y. (Yuetiva), McKenzie, A. (Andrew), Raj, T. (Towfique), Renton, A. (Alan), Budde, J. (John), Smith, A.V. (Albert), Fitzpatrick, A. (Annette), Bis, J.C. (Joshua), DeStefano, A.L. (Anita), Adams, H.H.H. (Hieab), Ikram, M.A. (Arfan), Lee, S.J. (Sven) van der, Del-Aguila, J.L. (Jorge L.), Fernandez, M.V. (Maria Victoria), Ibañez, L. (Laura), Sims, R. (Rebecca), Escott-Price, V. (Valentina), Mayeux, R. (Richard), Haines, J.L. (Jonathan), Farrer, L.A. (Lindsay), Pericak-Vance, M.A. (Margaret), Lambert, J.-C. (J.), Duijn, C.M. (Cornelia) van, Launer, L.J. (Lenore), Seshadri, S. (Sudha), Williams, J. (Julie), Amouyel, P. (Philippe), Schellenberg, G.D. (Gerard), Zhang, B. (Bin), Borecki, I.B. (Ingrid), Kauwe, J.S.K. (John S.K.), Cruchaga, C. (Carlos), Hao, K. (Ke), and Goate, A.M. (Alison)

Abstract

A genome-wide survival analysis of 14,406 Alzheimer's disease (AD) cases and 25,849 controls identified eight previously reported AD risk loci and 14 novel loci associated with age at onset. Linkage disequilibrium score regression of 220 cell types implicated the regulation of myeloid gene expression in AD risk. The minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, showed association with delayed AD onset and lower expression of SPI1 in monocytes and macrophages. SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability was enriched within the PU.1 cistrome, implicating a myeloid PU.1 target gene network in AD. Finally, experimentally altered PU.1 levels affected the expression of mouse orthologs of many AD risk genes and the phagocytic activity of mouse microglial cells. Our results suggest that lower SPI1 expression reduces AD risk by regulating myeloid gene expression and cell function.

Published
2017
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10. Clinicopathologic characteristics of Chinese hereditary non-polyposis colorectal cancer.

Author

Long Cui, S.C., Hei Ying Jin, S.C., Hui Yu Cheng, S.C., Yu Di Yan, S.C., Rong Gui Meng, S.C., and De Hong Yu, S.C.

Subjects
*COLON cancer, *CANCER, *CHINESE people, *DISEASES
Abstract

The aim of the present study was to examine the clinicopathologic characteristics of Chinese patients with hereditary non-polyposis colorectal cancer (HNPCC) and those with suspected (atypical) HNPCC. Personal and family cancer histories were obtained by reviewing the charts and interviewing the proband and participating relatives. Families were identified and classified into three groups by either the Amsterdam or Japanese criteria for HNPCC. Clinical characteristics including onset, localization, stage of colorectal cancer (CRC), tumor multiplicity, survival and mucinous histology were evaluated. Ninety-eight subjects comprising 92 CRC patients and six extracolonic cancer patients from 13 typical and 19 non-typical HNPCC kindreds were enrolled. There were 53 patients with CRC, one with both CRC and extracolonic cancer and five with extracolonic cancer in the typical HNPCC group, and in the atypical group there were 38 patients with CRC and one with extracolonic cancer. The average onset age of typical HNPCC and atypical HNPCC was 48 and 50 years, respectively, without statistical difference. There were no statistical differences in sex, pathological type, stage, site distribution of the tumor or survival between typical HNPCC and atypical HNPCC groups. There were 11.1% (6/54) metachronous CRC in the typical HNPCC group, and 7.9% (3/38) metachronous and 2.6% (1/38) synchronous CRC in the atypical HNPCC group. The Amsterdam criteria are important, but inappropriate for the establishing the clinical diagnosis of HNPCC in Chinese patients, with some atypical families that did not fulfil all the Amsterdam criteria probably possessing similar clinicopathogical features and genetic alterations. It seems that HNPCC should be considered in some suspected cases. [ABSTRACT FROM AUTHOR]

Published
2003
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