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Cystic kidney diseases encompass a range of genetic disorders in which the primary cilia of the cells are affected and thereby cysts form as a result. There are an increasing range of cystic renal diseases recognized due to the advances in genomics. The most common genetic kidney condition is autosomal dominant polycystic kidney disease (ADPKD). ADPKD leads to renal failure in adulthood. In children, hypertension is common and if treated, may slow down renal decline. The most common cystic kidney disease causing renal failure in children is autosomal recessive polycystic kidney disease (ARPKD). ARPKD also affects the liver. These conditions often have extra-renal features which also need to be addressed. Until recently, treatments were mainly supportive but now it is possible to slow down development of cyst formation and renal decline in ADPKD. This raises hope for treatment for other cystic renal conditions as more genes are identified and underlying mechanisms defined. [ABSTRACT FROM AUTHOR]

Neurofibromatosis is an autosomal dominant disorder characterized by tumors of the nervous system and skin. Plexiform neurofibromas are common complications of neurofibromatosis type 1 and can cause large facial deformities. Vascular anomalies are in turn a rare manifestation of neurofibromatosis. We present the case of a 48-year-old female patient with right hemifacial neurofibromatosis associated with venous vascular malformation, previously treated surgically and then with sclerosing agents, determining severe residual facial deformity. Her surgical approach using a modified facelift technique associated with partial tumor debulking and lipofilling seems to be a valid technical alternative for these highly complex cases that require a customized approach after exhaustive preoperative evaluation. [ABSTRACT FROM AUTHOR]

Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a rare paediatric disease primarily caused by sequence variants in PKHD1. ARPKD presents with considerable clinical variability relating to the type of PKHD1 sequence variant, but not its position. Animal models of Polycystic Kidney Disease (PKD) suggest a complex genetic landscape, with genetic modifiers as a potential cause of disease variability. To investigate in an unbiased manner the molecular mechanisms of ARPKD and identify potential indicators of disease severity, Whole Exome Sequencing (WES) and RNA-Sequencing (RNA-Seq) were employed on human ARPKD kidneys and age-matched healthy controls. WES confirmed the clinical diagnosis of ARPKD in our patient cohort consisting of ten ARPKD kidneys. Sequence variant type, nor position of PKHD1 sequence variants, was linked to disease severity. Sequence variants in genes associated with other ciliopathies were detected in the ARPKD cohort, but only PKD1 could be linked to disease severity. Transcriptomic analysis on a subset of four ARPKD kidneys representing severe and moderate ARPKD, identified a significant number of genes relating to WNT signalling, cellular metabolism and development. Increased expression of WNT signalling-related genes was validated by RT-qPCR in severe and moderate ARPKD kidneys. Two individuals in our cohort with the same PKHD1 sequence variants but different rates of kidney disease progression, with displayed transcriptomic differences in the expression of WNT signalling genes. ARPKD kidney transcriptomics highlights changes in WNT signalling as potentially significant in ARPKD manifestation and severity, providing indicators for slowing down the progression of ARPKD. [Display omitted] • Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a rare genetic kidney disease caused by PKHD1 mutations. • WES and RNA-Seq on ARPKD kidneys revealed no link between PKHD1 mutations and severity. • Mutations in ciliopathy genes discovered; only PKD1 correlated with disease severity. • Transcriptomics highlighted WNT signalling, metabolism and development genes in ARPKD. • Varied disease progression in individuals with identical PKHD1 mutations linked to WNT signalling differences. [ABSTRACT FROM AUTHOR]

Cystic kidney diseases encompass a range of genetic disorders in which the primary cilia of the cells are affected and thereby cysts form as a result. There are an increasing range of cystic renal diseases recognized due to the advances in genomics. The most common genetic kidney condition is autosomal dominant polycystic kidney disease (ADPKD). ADPKD leads to renal failure in adulthood. In children, hypertension is common and if treated, may slow down renal decline. The most common cystic kidney disease causing renal failure in children is autosomal recessive polycystic kidney disease (ARPKD). ARPKD also affects the liver. These conditions often have extra-renal features which also need to be addressed. Until recently, treatments were mainly supportive but now it is possible to slow down development of cyst formation and renal decline in ADPKD. This raises hope for treatment for other cystic renal conditions as more genes are identified and underlying mechanisms defined. [ABSTRACT FROM AUTHOR]

Abstract Primary autosomal recessive microcephaly (MCPH) is a rare hereditary disease characterized by congenitally small with brain circumference of the head below 3 standard deviations (SD). By far, 18 MCPH genes have been reported to be associated with the disease. SASS6 gene functioned in assembly of centrioles that the majority of MCPH genes present at the centrosome. There was only research reporting a homozygous missense mutation in SASS6 gene detected in a consanguineous Pakistani family. By conducting Whole-exome sequencing (WES) and Sanger sequencing on the family trio, we identified two novel splice site mutations c.127-13A>G and c.1867+2T>A in compound heterozygous hereditary form in the SASS6 gene. The two mutations were confirmed to alter mRNA splicing by RT-PCR assay. Our finding supported the role of SASS6 in the pathogenesis of microcephaly, expanding mutation spectrums and contributing to understanding of molecular mechanisms of MCPH. Highlights • We report SASS6 compound heterozygous mutations in a Chinese family with MCPH. • Our analysis is the second mutation report of SASS6 gene of the world. • c.127-13A>G and c.1867+2T>A are novel splice site mutations of SASS6. [ABSTRACT FROM AUTHOR]

Highlights • Two novel pathogenic variants in BRIP1 and TP53 were found. • Multigene panel testing provides more complete genetic information about patients. • Multigene panel testing should be considered in some families with a non-informative study in BRCA genes. Abstract Li-Fraumeni syndrome is an autosomal-dominant disorder caused by germline mutations in the tumour suppressor gene TP53. Here we report the case of a family whose index case was a woman diagnosed with bilateral breast cancer at the age of 18 and who had a non-informative result after BRCA1 and BRCA2 testing. After extending the study through multigene panel testing, two clinically relevant variants in the TP53 and BRIP1 genes, respectively, were found. Afterwards, the patient developed a glioblastoma. Both tumours were consistent with Li-Fraumeni syndrome. Thanks to the possibility of studying different genes related with hereditary breast and ovarian cancer, it was possible to find out the gene variant that caused the early onset cancers in the patient. Furthermore, genetic counselling was provided to the index case and her family. [ABSTRACT FROM AUTHOR]

Background Cystic fibrosis (CF) is an autosomal recessive disease associated with chronic airway infections by Staphylococcus aureus as one of the earliest and most prevalent pathogens. We conducted a retrospective study to determine the S. aureus infection status of CF patients treated since 1994 at two certified CF-centres in Münster, Germany, to get insights into the dynamics of S. aureus airway infection and the clinical impact on lung function on a long-term perspective. Materials and methods We used data from our microbiological database collected between 1994 and 2016 for patients treated at two centres in Münster, Germany, respectively, to determine the infection status for S. aureus . Furthermore, the resistance to selected antibiotics was determined for all patients’ isolates and for 15 patients on a longitudinal basis. In addition, the prevalence of adaptive phenotypes such as small colony variants (SCVs) and mucoid S. aureus was assessed. Results For this study, 2867 patient years with respiratory specimens (mean of 9.3 years for every patient, range 1–22 years) were evaluated for 283 CF patients (median age of 7 years at the beginning of the observation period, range 0–57 years, 51% male). 18% of patients were rarely infected by S. aureus (≤24% of observation years), 20% of patients intermittently (25–49%) and 61% persistently (≥50% of observation period). Susceptibility testing for 12969 S. aureus isolates resulted in resistance to methicillin in 9%, trimethoprim/sulfamethoxazole in 10%, levofloxacin in 14%, gentamicin in 20%, erythromycin and/or clindamycin in 30% and penicillin in 80% of all isolates. S. aureus isolates of 15 patients revealed dynamics of resistance with increase, decrease and loss of resistant isolates to the analysed antibiotics during the study period. SCVs were isolated at least once from 42% (n = 118) of patients and mucoid isolates from 2% (n = 7) of patients. In the last study year, 89 patients were infected by S. aureus only, 44 patients by S. aureus and Pseudomonas aeruginosa and 18 by P. aeruginosa only. Patients infected by S. aureus only were younger and had better lung function compared to the other two groups. Conclusions We determined a high percentage of patients with persistent S. aureus infection. During persistence, mostly fluctuation of resistance against various antibiotics was observed in the isolates indicating acquisition and loss of resistance genes by S. aureus . The prevalence of adaptive phenotypes during long-term persistence was high for SCVs (42% of patients), but low for mucoid isolates (2% of patients), which might be underestimated for mucoid phenotypes due to the retrospective study design and the difficulty to detect mucoid isolates in primary cultures. While patients with S. aureus only had better lung function and were younger, no difference was found between the group of P. aeruginosa and S. aureus co-infection and P. aeruginosa only with previous S. aureus infection. [ABSTRACT FROM AUTHOR]

Objective To assess the construct validity of the 10-Meter Walk Test (10mWT), Six-Minute Walk Test (6MWT), Berg Balance Scale (BERG), and Timed Up and Go (TUG) in adults with Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS), in addition to the interrater reliability of the 10mWT and 6MWT. Methods Reliability was determined using the intraclass correlation coefficient (ICC). Validity was determined first by correlating the 10mWT, 6MWT, BERG, and TUG with participant's age, lower limb coordination, and disease severity, and then by assessing their capacity to distinguish between participants based on sex and disease stages. Results Interrater reliability of the 10mWT at both comfortable and maximum speed as well as the 6MWT is excellent (ICC = 0.97–0.99). Construct validity of the four tests was confirmed, as showed by the high correlations with age, lower limb coordination, and overall disease severity ( ρ  = 0.64–0.97). Conclusions The four tests assessed for their metrological properties in this study showed to be valid instruments to use in the ARSACS population. The 10mWT and 6MWT are also highly reliable. BERG and TUG reliability will need to be assess in a future study. [ABSTRACT FROM AUTHOR]

Background The gene SYNE1 is highly expressed in the cerebellum and its dysfunction is related to an autosomal recessive ataxia ( SYNE1 -ataxia). The disease was firstly considered a pure cerebellar ataxia however, recent studies have described a broader clinical presentation, including motor neuron disease symptoms. Objectives To investigate cerebellar and potential extra-cerebellar changes in SYNE1 -ataxia using multimodal neuroimaging analyses . Methods Six patients completed clinical and imaging exams, and were compared to age-gender-matched healthy controls. Gray matter was analyzed using FreeSurfer and CERES for brain and cerebellum, respectively. White matter was analyzed with DTI-TBSS while we used SpineSeg for spinal cord analysis. Results We found significantly reduced cortical thickness ( p  < 0.05, FDR -corrected) in primary and association cortices, and volume reduction in subcortical structures, brainstem and cerebellum. White matter was found disrupted in both brain and cerebellum ( p  < 0.05, FWE -corrected). These results are consistent with the expression of the SYNE1 mRNA and its encoded protein in the brain. We failed to demonstrate spinal cord changes. Conclusions SYNE1- ataxia is, therefore, a relatively common cause of recessive ataxia characterized by complex multisystemic neurostructural changes consistent with the phenotypic heterogeneity and neuroimaging configures a potential marker of the disease. [ABSTRACT FROM AUTHOR]

Complex balanced autosomal translocation is rare and can lead to impaired spermatogenesis in males; however, its effects on oligozoospermia have rarely been reported. We report here two cases of rare complex balanced translocation in men with infertility. The karyotype of the first case was 46,XY,der(1)t(1;12)(p22;p11.2)ins(9;1)(p24;q25q23),der(9)ins(9;1),der(12)t(1;12)·ish der(1)t(1;12)(RP11-636B1+;RP11-659D23+)ins(9;1)(RP11-118P13+),der(9)ins(9;1),der(12)t(1;12). And the patient showed severe oligozoospermia with adult schizophrenia without other abnormalities. The karyotype of the second patient was 46,XY,der(5)t(5;11)(q14;p11.2),der(11)t(11;18)(p11.2;q11.2),der(18)t(5,18)(q14;p11.3)add(18)(q11.2?)·ish der(5)t(5;11)(RP11-846K3+,RP11-89B9+),der(11)t(11;18)(RP11-89B9-,RP11-170L12+,RP11-469N6+),der(18)t(5;18)(RP11-125L2+,RP11-29M13+)add(18)(q11.2?), and the patient displayed severe oligozoospermia without other abnormalities. The two cases were verified by fluorescent in situ hybridization, and no abnormalities were found by genome-wide copy number variation analysis. To our knowledge, these two cases of complex autosomal karyotypes have not been reported previously. Although rare, these cases suggest that complex balanced translocations may be important causes of oligozoospermia. We speculate that the balanced translocation hinders germ cell meiosis and causes impaired spermatogenesis. Accordingly, the two reported patients have very low probabilities of giving birth to a normal child; therefore, we suggest choosing donor semen or adopting a child. [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) features selective loss of dopaminergic neurons of the substantia nigra pars compacta accompanied by the accumulation and aggregation of alpha-synuclein in Lewy bodies. PTEN induced putative kinase 1 gene ( PINK1 ) mutations are the second most common genetic cause of autosomal recessive early-onset Parkinson’s disease (EOPD). A single nucleotide deletion in PINK1 exon 8 (c.1557delG) was identified in a consanguineous Chinese family with EOPD. The homozygous deletion was co-segregated with disease in the family and resulted in a frameshift after codon 520 with a premature termination at codon 522 (p.K520RfsX3). These findings have significant implications on genetic counseling for the family and may be helpful in considering potential pathogenesis-targeted and disease-modifying strategies which should further improve patient quality of life. [ABSTRACT FROM AUTHOR]

Objective Locus and allellic heterogeneity in polycystic kidney disease (PKD) is a great challenge in precision diagnosis. We aim to establish comprehensive methods to distinguish the pathogenic mutations from the variations in PKD1 , PKD2 and PKHD1 genes in a limited time and lay the foundation for precisely prenatal diagnosis, preimplantation genetic diagnosis and presymptom diagnosis of PKD. Methods Nested PCR combined with direct DNA sequencing were used to screen variations in PKD1 , PKD2 and PKHD1 genes. The pathogenicity of de novel variations was assessed by the comprehensive methods including clinic data and literature review, databases query, analysis of co-segregation of the variants with the disease, variant frequency screening in the population, evolution conservation comparison, protein structure analysis and splice sites predictions. Results 17 novel mutations from 15 Chinese Han families were clarified including 10 mutations in PKD1 gene and 7 mutations in PKHD1 gene. The novel mutations were classified as 4 definite pathogenic, 2 highly likely pathogenic, 4 likely pathogenic, 7 indeterminate by the comprehensive analysis. The results were verified the truth by the follow-up visits. Conclusions The comprehensive methods may be useful in distinguishing the pathogenic mutations from the variations in PKD1 , PKD2 and PKHD1 genes for prenatal diagnosis and presymptom diagnosis of PKD. Our results also enriched PKD genes mutation spectrum and evolved possible genotype-phenotype correlations of Chinese Han population. [ABSTRACT FROM AUTHOR]

Mutations in the ganglioside-induced differentiation-associated protein 1 gene ( GDAP1 ) cause rare subtypes of Charcot–Marie–Tooth disease (CMT2K and CMT4A). CMT2K is an axonal neuropathy while CMT4A is a demyelinating type. In a series of 169 Chinese CMT patients (79 CMT1, 52 CMT2 and 38 unclassified), four unrelated patients (2.37%) were identified with GDAP1 mutations, including two with autosomal recessive CMT2K (AR-CMT2K) and two dominant CMT2K (AD-CMT2K). All patients had disease onset before 5 years of age, and presented with muscle weakness, atrophy, and mild sensory disturbance in distal limbs. Motor nerve conduction velocities of the median nerve were within normal ranges, and compound muscle action potential ranged from 1.5 to 3.8 mV. Sural nerve biopsy revealed loss of large myelinated fibers with regeneration clusters and a few onion bulbs. Electron microscopy showed mitochondrial aggregation in both axons and Schwann cells, and neurofilament accumulation in giant unmyelinated fibers. The p.H256R mutation was found in all patients with GDAP1 compound heterozygous mutations, suggesting that it might be a common mutation in Chinese patients. This study observed no difference in the disease onset, phenotype severity, electrophysiological findings, or pathological changes between AR-CMT2K and AD-CMT2K patients. [ABSTRACT FROM AUTHOR]

Knobloch syndrome [OMIM: (KNO1) #267750] is a rare and clinically heterogeneous autosomal recessive disorder caused by mutations in COL18A1 . Knobloch syndrome is characterised by abnormalities of the eye and occipital skull defects however the full phenotypic spectrum is yet to be defined. This report describes a family of four affected sisters with polymicrogyria, refractory seizures, and intellectual impairment of varying severity with a Lennox-Gastaut phenotype, and complex eye abnormalities where a syndromic diagnosis was not initially made. Whole exome sequencing of two affected sisters followed by filtering for rare and potentially disease causing variants in all genes identified compound heterozygous variants in NM_030582.3 ( COL18A1 ): c.3690G > A: p.(Trp1230*) and NM_030582.3 ( COL18A1 ): c.4063_4064delCT: p.(Leu1355Valfs*72). The two variants co-segregated with the affected individuals in the family. Identification of COL18A1 mutations in individuals with a Lennox-Gastaut phenotype and anterior polymicrogyria but lacking the classical occipital encephalocele expands the COL18A1 clinical spectrum. [ABSTRACT FROM AUTHOR]

Hereditary tyrosinemia type 1 (HT1) is a severe human autosomal recessive disorder caused by the deficiency of fumarylacetoacetate hydroxylase (FAH), an enzyme catalyzing the last step in the tyrosine degradation pathway. Lack of FAH causes accumulation of toxic metabolites (fumarylacetoacetate and succinylacetone) in blood and tissues, ultimately resulting in severe liver and kidney damage with onset that ranges from infancy to adolescence. This tissue damage is lethal but can be controlled by administration of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), which inhibits tyrosine catabolism upstream of the generation of fumarylacetoacetate and succinylacetone. Notably, in animals lacking FAH, transient withdrawal of NTBC can be used to induce liver damage and a concomitant regenerative response that stimulates the growth of healthy hepatocytes. Among other things, this model has raised tremendous interest for the in vivo expansion of human primary hepatocytes inside these animals and for exploring experimental gene therapy and cell-based therapies. Here, we report the generation of FAH knock-out rabbits via pronuclear stage embryo microinjection of transcription activatorlike effector nucleases. FAH-/- rabbits exhibit phenotypic features of HT1 including liver and kidney abnormalities but additionally develop frequent ocular manifestations likely caused by local accumulation of tyrosine upon NTBC administration. We also show that allogeneic transplantation of wildtype rabbit primary hepatocytes into FAH-/- rabbits enables highly efficient liver repopulation and prevents liver insufficiency and death. Because of significant advantages over rodents and their ease of breeding, maintenance, and manipulation compared with larger animals including pigs, FAH-/- rabbits are an attractive alternative for modeling the consequences of HT1. [ABSTRACT FROM AUTHOR]

Abstract Mosaic variegated aneuploidy syndrome (MVA) is a rare autosomal recessive disorder characterized by random chromosome gains and losses. Mutations in BUB1B and CEP57 genes have been involved in MVA. Here we report on a male child with MVA due to c.915_925dupCAATGTTCAGC mutation in the CEP57 gene. Our patient was homozygous for this mutation and he is the first case with rhizomelic shortening of both the upper and lower limbs and mild respiratory insufficiency due to a narrow thorax. It is also the second MVA Mexican family reported with this mutation that lives in the northwestern region of Mexico, suggesting a "local founding effect". Additional cases are needed to better understand the MVA genotype-phenotype relationship. [ABSTRACT FROM AUTHOR]

Autosomal recessive polycystic kidney disease (ARPKD) a rare genetic disorder, described by formation of cysts in the kidney. A targeted customized sequencing of genes implicated in ARPKD phenotype was performed to identify candidate variants using the Ion torrent PGM next-generation sequencing. The results identified likely pathogenic disease causing variants during the validation process. Four potential pathogenic variants [c.4870C>T, p.(Arg1624Trp)], [c.5725C>T, p.(Arg1909Trp)], c.1736C > T, p.(Thr579Met)] and [(c.10628T > G), p.(Leu3543Trp)] were observed in PKHD1 gene among 12 out of 18 samples. The rest of the patient samples also showed few variants in ADPKD (Autosomal Dominant Polycystic Kidney Disease) disease causing genes PKD1 and PKD2 i.e. [c.12433G > A, p.(Val4145Ile)] and [c.1445T > G, p.(Phe482Cys)], respectively. All causative variants were validated by capillary sequencing, confirming the presence of a novel homozygous variants [c.10628T > G, p.(Leu3543Trp)] found in exon 61 of a male proband. All potentially deleterious variants identified in PKHD1, PKD1, and PKD2 gene, also exhibited pathologically or clinically significance based on the computational predictions involved in predicting the impact of non-synonymous SNPs (nsSNPs) on protein function such as Sorting Intolerant From Tolerant (SIFT) and Polymorphism Phenotyping (PolyPhen2). SIFT classified 50% of our nsSNPs as “deleterious”, while PolyPhen2 identified 45% of our nsSNPs as “Probably damaged” and the results from both programs were largely complementary. Taken together, these results suggest that the NGS strategies provide a fast, accurate and cost-effective molecular diagnostic tool for identifying mutations in targeted genes sequence analysis. [ABSTRACT FROM AUTHOR]

Glycogen storage disease type IV (GSD IV) is an autosomal recessive disorder causing polyglucosan storage in various tissues. Neuromuscular forms present with fetal akinesia deformation sequence, lethal myopathy, or mild hypotonia and weakness. A 3-year-old boy presented with arthrogryposis, motor developmental delay, weakness, and rigid spine. Whole body MRI revealed fibroadipose muscle replacement but sparing of the sartorius, gracilis, adductor longus and vastus intermedialis muscles. Polyglucosan bodies were identified in muscle, and GBE1 gene analysis revealed two pathogenic variants. We describe a novel neuromuscular GSD IV phenotype and confirm the importance of muscle morphological studies in early onset neuromuscular disorders. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) is the most common autosomal recessive disease in the Caucasian population, but it has also been widely diagnosed in the Mexican population. Production of viscous secretions affects the secretory epithelia and the respiratory condition usually leads to death. The relationship between the CFTR genotype and the disease phenotype is not well understood. Other risk factors such as genetic and autoimmune influence the development of this disease. We analyzed the PTPN22 R620W polymorphism (+1858 C/T, rs2476601) in 78 DNA samples from CF patients and 232 healthy controls from northeast Mexico using the polymerase chain reaction-restriction fragment length (PCR-RFLP) method. The C allele and the CC genotype were the most frequently detected in controls (CC genotype 96.12%; C allele 98.06%) compared with CF patients (CC genotype 88.46%, C allele 93.59%). A statistically significant association for the CT + TT genotypes ( p = 0.012, OR = 3.232) as well as for the mutant T allele ( p = 0.005, OR = 3.463) was found when comparing CF patients with controls. A significant association was found between the rs2476601 polymorphism of the PTPN22 gene and CF in Mexican patients. Further studies are necessary to understand the influence of this variant on lung neutrophil function and disease development. [ABSTRACT FROM AUTHOR]

Background: Kufor-Rakeb syndrome (KRS) is an autosomal recessive, juvenile-onset Parkinson's disease (PD) caused by loss-of-function mutations in ATP13A2 (PARK9). Impaired energy metabolism is considered a pathogenic mechanism in PD and mitochondrial dysfunction resulting from Zn(2+) dyshomeostasis has been found in KRS patient-derived cells. In addition to mitochondrial energy production, glycolysis plays an important role in cellular energy metabolism and glucose hypometabolism has been reported in PD. However, glycolytic status in KRS remains undetermined despite its potential importance.Methods: We assessed glycolytic function in ATP13A2-deficient KRS patient-derived human olfactory neurosphere cells and fibroblasts and determined the effect of pyruvate supplementation on improving cellular energy production.Results: We found impaired extracellular acidification, reduction in pyruvate production and a decrease in the NAD(+)/NADH ratio, indicative of glycolytic dysfunction. In addition, gene expression analysis revealed an altered expression profile for several glycolytic enzymes. Glycolytic dysfunction was aggravated when the intracellular Zn(2+) concentration was increased, while ATP13A2 overexpression and pyruvate supplementation blocked the observed Zn(2+)-mediated toxicity. Moreover, supplementation with pyruvate significantly increased basal mitochondrial ATP production and abolished Zn(2+)-induced cell death.Conclusions: These findings indicate that glycolytic dysfunction contributes to pathogenesis and pyruvate supplementation improves overall cellular bioenergetics in our KRS patient-derived cell model, highlighting a therapeutic potential. [ABSTRACT FROM AUTHOR]

Autosomal recessive polycystic kidney disease (ARPKD) is usually detected late in pregnancies in embryos with large echogenic kidneys accompanied by oligohydramnios. Hundreds of private pathogenic variants have been identified in the large PKHD1 gene in various populations. Yet, because of the large size of the gene, segregation analysis of microsatellite polymorphic markers residing in the PKDH1 locus has commonly been utilized for prenatal diagnosis. Keeping in mind the limitations of this strategy, we utilized it for testing 7 families with affected fetuses or newborns, of which in 5 at least one parent was Ashkenazi, and identified that the same haplotype was shared by the majority of the Ashkenazi parents (7/9). This led us to suspect that they carry the same founder mutation. Whole Exome analysis of DNA from a fetus of one of the families detected an already known pathogenic variant c.3761_3762delCCinsG, an indel variant resulting in frameshift (p.Ala1254GlyfsX49). This variant was detected in 9 parents (5 families), of them 7 individuals were Ashkenazi and one Moroccan Jew who shared the same haplotype, and one Ashkenazi, who carried the same variant on a recombinant haplotype. Screening for this variant in 364 Ashkenazi individuals detected 2 carriers. These findings suggest that although c.3761_3762delCCinsG is considered one of the frequent variants detected in unrelated individuals, and was thought to have occurred independently on various haplotypes, it is in fact a founder mutation in the Ashkenazi population. [ABSTRACT FROM AUTHOR]

Two themes are emerging regarding the molecular genetic aetiology of intelligence. The first is that intelligence is influenced by many variants and those that are tagged by common single nucleotide polymorphisms account for around 30% of the phenotypic variation. The second, in line with other polygenic traits such as height and schizophrenia, is that these variants are not randomly distributed across the genome but cluster in genes that work together. Less clear is whether the very low range of cognitive ability (intellectual disability) is simply one end of the normal distribution describing individual differences in cognitive ability across a population. Here, we examined 40 genes with a known association with non-syndromic autosomal recessive intellectual disability (NS-ARID) to determine if they are enriched for common variants associated with the normal range of intelligence differences. The current study used the 3511 individuals of the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium. In addition, a text mining analysis was used to identify gene sets biologically related to the NS-ARID set. Gene-based tests indicated that genes implicated in NS-ARID were not significantly enriched for quantitative trait loci (QTL) associated with intelligence. These findings suggest that genes in which mutations can have a large and deleterious effect on intelligence are not associated with variation across the range of intelligence differences. [ABSTRACT FROM AUTHOR]

Charcot–Marie–Tooth disease is a group of genetically heterogeneous disorders characterized by a sensorimotor polyneuropathy with subsequent muscle atrophy, areflexia, and sensory loss. More than 60 genes have been linked to Charcot–Marie–Tooth phenotypes, including IGHMBP2 . Until recently, mutations in IGHMBP2 were exclusively associated with spinal muscular atrophy with respiratory distress (SMARD1). We present a sibling pair with a novel homozygous truncating mutation in IGHMBP2 . The patients presented with childhood-onset distal weakness, wasting in the upper and lower limbs, areflexia and decreased sensation, but no respiratory involvement. Exome sequencing was performed and a homozygous variant was identified (c.2601_2604del; p.Lys868Profs*109). Sanger sequencing confirmed the presence of this variant in a homozygous state in the two affected siblings, while both parents were heterozygous. Further analyses showed decreased mRNA and IGHMBP2 protein in a lymphoblast cell line derived from one of the siblings. We demonstrate the utility of next-generation sequencing in reaching a molecular diagnosis for a heterogeneous condition such as Charcot–Marie–Tooth. Taken together, our data and that from the literature suggest that the spectrum of clinical presentations associated with mutations in IGHMBP2 may be secondary, at least in part, to the amount of residual protein. [ABSTRACT FROM AUTHOR]

Wilson disease is an infrequent autosomal recessive disorder caused by mutations in the ATP7B gene (13q14.3) producing pathologic phenotypes due to copper accumulation in critical tissues. The aim of the research was to probe Wilson disease genetic epidemiology in Venezuela, through the identification in diagnosed index cases, of ATP7B locus mutations, their geographic distribution, frequency, in-phase haplotypes and probable ethnic ancestry. During the last three decades 33 independent Wilson disease families from the country at large were ascertained and diagnosed through severely reduced ceruloplasmin activity, higher urinary copper excretion, and specific clinical signs. Molecular studies of the ATP7B gene were accomplished in 26 of the families. Disease prevalence was estimated as 1:94,000 families between 1985 and 2013, showing geographic aggregation in the state of Zulia with 1:27,000 families in it. DNA analysis in 26 families revealed 13 different mutations. The c.3402delC was the most frequent one (26.9%), presenting two independent in-phase haplotypes, both of likely European descent; which is followed by the not previously reported p.G691V (9.6%) and by the frequent European H1069Q (7.7%). Known mutations c.51 + 4A > T, c.1285 + 5G > T, M645R, T788I, V845SfsX28, T977M, L1088X, T1220M, R1319X and a novel P767L showed frequencies between 5.8 and 1.9%. Despite the ample mutation heterogeneity for Wilson disease in the country, the findings provide a diagnostic algorithm to ease mutation assessment in new patients; the predominant c.3402delC displayed wide geographic distribution and two genetic origins. [ABSTRACT FROM AUTHOR]

Background Rh null is a rare autosomal recessive phenotype, which is characterized by the lack of Rh antigen expression on the red blood cells (RBCs). Rh null of the regulator type is caused by RHAG mutation. In this study, a novel nonsense mutation in RHAG gene was identified in a Chinese Rh null individual. Objectives and methods Rh phenotypes of the Rh null individual and his family members were typed by standard serological methods. DNA sequences of all ten exons of RHAG gene were analyzed using genomic DNA by polymerase chain reaction (PCR) and direct-sequencing. Results Serological testing results showed a D-C-c-E-e- phenotype in the proband. Molecular analyses revealed a 540C > A mutation in exon 4 of RHAG gene was present at the homozygous state in the proband. His parents were heterozygous for the mutation, and his brother didn’t carry the mutation. The 540C > A mutation was nonsense mutation, which led to a premature stop codon (Tyr180stop). Conclusion These results indicated that the 540C > A nonsense mutation in RHAG gene caused the regulator type of Rh null phenotype in a Chinese individual. Our results contributed to a greater understanding of the genetic mechanisms of Rh null phenotype. [ABSTRACT FROM AUTHOR]

Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency is an autosomal recessive disorder caused by mutations in the CYP21A2 gene. Females affected with classical CAH are at risk for genital ambiguity, but can be treated in utero with dexamethasone before 9 gestational weeks to prevent virilization. Early genetic diagnosis is unavailable through current invasive methods of chorionic villus sampling and amniocentesis. New developments in prenatal genetic testing utilize fetal DNA extracted from maternal blood through noninvasive methods, which allow the determination of fetal gender and the diagnosis of CAH at an early gestational age (<9 weeks). Noninvasive prenatal diagnosis allows for the establishment of early and effective management plans in fetuses at risk for CAH and avoids unnecessary prenatal dexamethasone treatment [ABSTRACT FROM AUTHOR]

Autosomal recessive polycystic kidney disease (ARPKD) is a rare hereditary renal cystic disease involving multiple organs, mainly the kidney and liver. Parents who had an affected child with ARPKD are in strong demand for an early and reliable prenatal diagnosis to guide the future pregnancies. Here we provide an example of prenatal diagnosis of an ARPKD family where traditional antenatal ultrasound examinations failed to produce conclusive results till 26th week of gestation. Compound heterozygous mutations c.274C>T (p.Arg92Trp) and c.9059T>C (p.Leu3020Pro) were identified using targeted exome sequencing in the patient and confirmed by Sanger sequencing. Further, the mother and father were revealed to be carriers of heterozygous c.274C>T and c.9059T>C mutations, respectively. Molecular prenatal diagnosis was performed for the current pregnancy by direct sequencing plus linkage analysis. Two mutations identified in the patient were both found in the fetus. In conclusion, compound heterozygous PKHD1 mutations were elucidated to be the molecular basis of the patient with ARPKD. The newly identified c.9059T>C mutation in the patient expands mutation spectrum in PKHD1 gene. For those ultrasound failed to provide clear diagnosis, we propose the new prenatal diagnosis procedure: first, screening underlying mutations in PKHD1 gene in the proband by targeted exome sequencing; then detecting causative mutations by direct sequencing in the fetal DNA and confirming results by linkage analysis. [ABSTRACT FROM AUTHOR]

Polycystic kidney disease (PKD) is an incurable genetic disorder that is characterized by multiple benign cysts. As PKD advances, cyst growth increases kidney volume, decreases renal function, and may lead to end-stage renal disease; however, in a PKD rat model, feeding soy protein isolate (SPI) reduced cyst proliferation and growth. The n-3 polyunsaturated fatty acids (PUFAs) are noted for their anti-inflammatory actions. Therefore, diet therapy could offer a potentially efficacious, safe, and cost-effective strategy for treating PKD. The objective of this study was to investigate the role of soy protein and/or n-3 PUFAs on PKD progression and severity in the rat model of autosomal recessive PKD. We hypothesized that the antiproliferative and anti-inflammatory actions associated with soy protein and n-3 PUFA supplementation will attenuate PKD progression in female PCK rats. For 12weeks, young (age, 28 days) female PCK rats were randomly assigned (n=12/group) to 4 different diets: casein±corn oil, casein±soybean oil, SPI±soybean oil, or SPI±1:1 soybean/salmon oil (SPI±SB). The feeding of the different protein and lipid sources had no significant effect on relative kidney weight. Histologic evaluation showed no significant differences in cortical or medullary cyst size, interstitial inflammation, and fibrosis among diet groups. However, rats fed SPI±SB diet had cortical cyst obstruction and the highest (P<.01) serum blood urea nitrogen concentration. Rats fed SPI±SB diet had the highest (P<.001) renal docosahexaeonic acid, but there were no significant differences in renal tissue inflammation and proliferation gene expression among the diet groups. Based on these results, dietary soy protein and/or n-3 PUFAs did not attenuate disease progression or severity in the female PCK rat model of autosomal recessive PKD. [ABSTRACT FROM AUTHOR]

Abstract: Dysfunction of TMEM70 disrupts the biogenesis of ATP synthase and represents the frequent cause of autosomal recessive encephalocardiomyopathy. We used tagged forms of TMEM70 and demonstrated that it has a hairpin structure with the N- and C-termini oriented towards the mitochondrial matrix. On BN-PAGE TMEM70 was detected in multiple forms including dimers and displayed partial overlap with assembled ATP synthase. Immunoprecipitation studies confirmed mutual interactions between TMEM70 molecules but, together with immunogold electron microscopy, not direct interaction with ATP synthase subunits. This indicates that the biological function of TMEM70 in the ATP synthase biogenesis may be mediated through interaction with other protein(s). [Copyright &y& Elsevier]

Abstract: PINK1 mutations cause autosomal recessive forms of Parkinson disease (PD). Previous studies suggest that the neuroprotective function of wild-type (WT) PINK1 is related to mitochondrial homeostasis. PINK1 can also localize to the cytosol; however, the cytosolic function of PINK1 has not been fully elucidated. In this study we demonstrate that the extramitochondrial PINK1 can regulate tyrosine hydroxylase (TH) expression and dopamine (DA) content in dopaminergic neurons in a PINK1 kinase activity-dependent manner. We demonstrate that overexpression of full-length (FL) WT PINK1 can downregulate TH expression and DA content in dopaminergic neurons. In contrast, overexpression of PD-linked G309D, A339T, and E231G PINK1 mutations upregulates TH and DA levels in dopaminergic neurons and increases their vulnerability to oxidative stress. Furthermore transfection of FL WT PINK1 or PINK1 fragments with the PINK1 kinase domain can inhibit TH expression, whereas kinase-dead (KD) FL PINK1 or KD PINK1 fragments upregulate TH level. Our findings highlight a potential novel function of extramitochondrial PINK1 in dopaminergic neurons. Deregulation of these functions of PINK1 may contribute to PINK1 mutation-induced dopaminergic neuron degeneration. However, deleterious effects caused by PINK1 mutations may be alleviated by iron-chelating agents and antioxidant agents with DA quinone-conjugating capacity. [Copyright &y& Elsevier]

Abstract: Background: Argininosuccinate synthetase deficiency (citrullinemia type 1) is a rare autosomal recessive disorder of the urea cycle characterized by elevated concentrations of citrulline, ammonia, and orotic acid, manifesting with acute hyperammonemic crises, usually early in life, with concurrent neurologic deterioration. Only a few cases of citrullinemia type 1 have been documented from mainland China. Prenatal diagnosis has not been performed. Methods: A Chinese family affected by citrullinemia type 1 was studied. The proband, a girl, was the second child born to a non-consanguineous couple. Her elder brother died at 19months due to coma and liver dysfunction of unknown cause. The proband was admitted because of severe mental retardation and lethargy at the age of 15months. Initial laboratory results revealed hyperammonaemia, hypercitrullinemia (928.771μmol/L, normal 5.0–25.0μmol/L) and orotic aciduria, supporting the diagnosis of citrullinemia type 1. Subsequently, the mother presented at 15weeks of pregnancy seeking for genetic counseling and prenatal diagnosis. ASS1 gene in the blood leukocytes of the family members and amniocytes was performed by direct sequencing. Results: On the ASS1 gene of the proband, a novel mutation, T1009C (C337R), and a previously reported mutation G847A (E283K) were identified. Each parent carries one of two mutations. G847A and T1009C mutations were detected in amniocytes, as same as the proband of the family. The result revealed that the fetus was affected by argininosuccinate synthetase deficiency. The parents chose to have a termination of the pregnancy. Conclusions: Prenatal diagnosis for citrullinemia type 1 was performed in a Chinese family using gene analysis. T1009C (C337R), a novel mutation of ASS1, was identified. [Copyright &y& Elsevier]

Summary: Background: Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown cause. We aimed to identify the genetic basis of this syndrome by sequencing most coding exons in affected individuals. Methods: Through a search of available case studies and communication with collaborators, we identified families that included at least one individual with at least three of the five main features of the DOORS syndrome: deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. Participants were recruited from 26 centres in 17 countries. Families described in this study were enrolled between Dec 1, 2010, and March 1, 2013. Collaborating physicians enrolling participants obtained clinical information and DNA samples from the affected child and both parents if possible. We did whole-exome sequencing in affected individuals as they were enrolled, until we identified a candidate gene, and Sanger sequencing to confirm mutations. We did expression studies in human fibroblasts from one individual by real-time PCR and western blot analysis, and in mouse tissues by immunohistochemistry and real-time PCR. Findings: 26 families were included in the study. We did exome sequencing in the first 17 enrolled families; we screened for TBC1D24 by Sanger sequencing in subsequent families. We identified TBC1D24 mutations in 11 individuals from nine families (by exome sequencing in seven families, and Sanger sequencing in two families). 18 families had individuals with all five main features of DOORS syndrome, and TBC1D24 mutations were identified in half of these families. The seizure types in individuals with TBC1D24 mutations included generalised tonic-clonic, complex partial, focal clonic, and infantile spasms. Of the 18 individuals with DOORS syndrome from 17 families without TBC1D24 mutations, eight did not have seizures and three did not have deafness. In expression studies, some mutations abrogated TBC1D24 mRNA stability. We also detected Tbc1d24 expression in mouse phalangeal chondrocytes and calvaria, which suggests a role of TBC1D24 in skeletogenesis. Interpretation: Our findings suggest that mutations in TBC1D24 seem to be an important cause of DOORS syndrome and can cause diverse phenotypes. Thus, individuals with DOORS syndrome without deafness and seizures but with the other features should still be screened for TBC1D24 mutations. More information is needed to understand the cellular roles of TBC1D24 and identify the genes responsible for DOORS phenotypes in individuals who do not have a mutation in TBC1D24. Funding: US National Institutes of Health, the CIHR (Canada), the NIHR (UK), the Wellcome Trust, the Henry Smith Charity, and Action Medical Research. [Copyright &y& Elsevier]

ARPKD is a genetically inherited kidney disease that manifests by bilateral enlargement of cystic kidneys and liver fibrosis. It shows a range of severity, with 30% of individuals dying early on and the majority having good prognosis if they survive the first year of life. The reasons for this variability remain unclear. Two genes have been shown to cause ARPKD when mutated, PKHD1 , mutations in which lead to most of ARPKD cases and DZIP1L , which is associated with moderate ARPKD. This mini review will explore the genetics of ARPKD and discuss potential genetic modifiers and phenocopies that could affect diagnosis. • Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a rare, genetically inherited kidney disease. • It is caused by mutations in PHKD1 and DZIP1L , the proteins of both of which localise to cilia. • Variability in ARPKD severity is often observed and genetics can help us understand the variable manifestation mechanisms. • Mutation characteristics and genetic modifiers such as ATMIN may also assist in predicting ARPKD progression. [ABSTRACT FROM AUTHOR]

Abstract: Homozygosity mapping and exome sequencing in two affected siblings of a consanguineous family with mild intellectual disability, spastic paraplegia, and strabismus revealed a homozygous premature stop mutation at codon 139 of C12ORF65. Two previous studies reported truncating mutations at positions 84 and 132 of the protein. However, symptoms of the referred patients were only partially overlapping. Considering our findings, we now conclude that truncating mutations in C12ORF65 lead to a variable phenotype with intellectual disability, spastic paraplegia, and ophthalmoplegia as common symptoms. Further, we confirm a genotype–phenotype correlation between increasing length of the truncated protein and decreasing severity of symptoms. [Copyright &y& Elsevier]

Abstract: Sickle cell anemia (SCA) is an autosomal recessive disorder, with Mendelian inheritance pattern, caused by a missense mutation in the β-polypeptide chain of the hemoglobin B. SCA preferentially affects populations in countries where malaria was/is present (e.g. Africa, USA, Brazil). Thereby, in USA, the incidence of SCA is relatively high, around 1/500, and the prevalence is about 1/1000. In Brazil, SCA represents a major public health problem with an incidence ranging from 1/2000 to 1/600 depending on the regions. Homozygotic patients present more severe medical conditions and reduced life expectancy than heterozygous individuals who generally are asymptomatic. Eventually, this life-threatening disease displays a complex etiology owing to heterogeneous phenotypes and clinical outcomes, subsequently affecting the management of the patients. One of the most critical complications associated with SCA is stroke, a leading neurologic cause of death and disability. About 24% of SCA patients have a stroke by the age of 45 and 11% by the age of 20. From the general population, twin and familial aggregation studies as well as genome-wide association studies (GWAS), mostly in pediatric populations with ischemic stroke, showed that the risk of stroke has a substantial genetic component. Nevertheless, to fully characterize genomic contributors of stroke and permit reliable personalized medicine, multidisciplinary studies incorporating knowledge from clinical medicine, epidemiology, genetics, and molecular biology, are required. In this manuscript, stroke in SCA patients is extensively reviewed with emphasis to the US and Brazilian populations. Recent advances in genomics analysis of stroke in SCA patients are highlighted. [Copyright &y& Elsevier]

Abstract: Mutations in the FH gene cause the deficiency of the enzyme fumarase (fumarate hydratase, EC 4.2.1.2) which result in autosomal recessive fumaric aciduria in early childhood with failure to thrive, seizures, developmental delay, mental retardation, hypotonia and sometimes with polycythemia, leukopenia, and neutropenia. Many children with fumarate hydratase deficiency do not survive infancy or childhood; those surviving beyond childhood have severe psychomotor retardation. Recently, FH gene was also identified as a “non-classical” tumor suppressor gene and heterozygous mutations were shown to cause multiple cutaneous and uterine leiomyomas as well as hereditary leiomyomatosis and renal cell cancer. A male patient who was referred to investigate the etiology of psychomotor retardation was later diagnosed to have fumaric aciduria due to the combination of a previously known (c.1431_1433dupAAA) and a novel (c.782G>T) mutation. The patient had an unusually mild clinical course without acidotic attacks. Interestingly his father who was heterozygous for the c.1431_1433dupAAA mutation in the FH gene had cutaneous leiomyoma. [Copyright &y& Elsevier]

Gain-of-function mutations in the canonical transient receptor potential 6 (TRPC6) gene are a cause of autosomal dominant focal segmental glomerulosclerosis (FSGS). The mechanisms whereby abnormal TRPC6 activity results in proteinuria remain unknown. The ERK1/2 MAPKs are activated in glomeruli and podocytes in several proteinuric disease models. We therefore examined whether FSGS-associated mutations in TRPC6 result in activation of these kinases. In 293T cells and cultured podocytes, overexpression of gain-of-function TRPC6 mutants resulted in increased ERK1/2 phosphorylation, an effect dependent upon channel function. Pharmacologic inhibitor studies implicated several signaling mediators, including calmodulin and calcineurin, supporting the importance of TRPC6- mediated calcium influx in this process. Through medium transfer experiments, we uncovered two distinct mechanisms for ERK activation by mutant TRPC6, a cell-autonomous, EGF receptor-independent mechanism and a non-cell-autonomous mechanism involving metalloprotease-mediated release of a presumed EGF receptor ligand. The inhibitors KN-92 and H89 were able to block both pathways in mutant TRPC6 expressing cells as well as the prolonged elevation of intracellular calcium levels upon carbachol stimulation seen in these cells. However, these effects appear to be independent of their effects on calcium/ calmodulin-dependent protein kinase II and PKA, respectively. Phosphorylation of Thr-70, Ser-282, and Tyr-31/285 were not necessary for ERK activation by mutant TRPC6, although a phosphomimetic TRPC6 S282E mutant was capable of ERK activation. Taken together, these results identify two pathways downstream of mutant TRPC6 leading to ERK activation that may play a role in the development of FSGS. [ABSTRACT FROM AUTHOR]

Abstract: Background: Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the genes coding for the low density lipoprotein receptor (LDLR), proprotein convertase subtilisin/kexin type-9 (PCSK9) or apo-lipoprotein B-100 (APOB). The aim of the present work was to determine the genetic basis of dyslipidemia in 11 unrelated Pakistani families. Methods: High resolution melting (HRM), sequencing and restriction fragment length polymorphism (RFLP). Results: Probands were screened for the promoter and all coding regions, including intron/exon boundaries, of LDLR and PCSK9 and part of exon 26 of APOB including p.(R3527Q). Two families were identified with previously unreported LDLR mutations (c.1019_1020delinsTG, p.(C340L) and c.1634G>A, p.(G545E)). Both probands had tendon xanthomas or xanthelasma and/or a history of cardiovascular disease. Co-segregation with hypercholesterolemia was demonstrated in both families. In silico studies predicted these variations to be damaging. In two families, novel PCSK9 variations were identified (exon2; c.314G>A, p.(R105Q) and exon3; c.464C>T, p.(P155L)). In silico studies suggested both were likely to be damaging, and family members carrying the p.(105Q) allele had lower total cholesterol levels, suggesting this is a loss-of-function mutation. For c.464C>T p.(P155L) the small number of relatives available precluded any strong inference. Conclusion: This report brings to seven the number of different LDLR mutations reported in FH patients from Pakistan and, as expected in this heterogeneous population, no common LDLR mutation has been identified. [Copyright &y& Elsevier]

Abstract: Hermansky–Pudlak syndrome (HPS) is a group of rare autosomal recessive disorders characterized by oculocutaneous albinism, a bleeding tendency, and sporadic pulmonary fibrosis, granulomatous colitis or infections. Nine HPS-causing genes have been identified in humans. HPS-1 is the most severe subtype with a prevalence of ~1/1800 in northwest Puerto Rico due to a founder mutation in the HPS1 gene. Mutations in HPS genes affect the biogenesis of lysosome-related organelles such as melanosomes in melanocytes and platelet dense granules. Two of these genes (HPS1 and HPS4) encode the HPS1 and HPS4 proteins, which assemble to form a complex known as Biogenesis of Lysosome-related Organelle Complex 3 (BLOC-3). We report the identification of the interacting regions in HPS1 and HPS4 required for the formation of this complex. Two regions in HPS1, spanning amino acids 1–249 and 506–700 are required for binding to HPS4; the middle portion of HPS1 (residues 250–505) is not required for this interaction. Further interaction studies showed that the N-termini of HPS1 and HPS4 interact with each other and that a discrete region of HPS4 (residues 340–528) interacts with both the N- and C-termini of the HPS1 protein. Several missense mutations found in HPS-1 patients did not affect interaction with HPS4, but some mutations involving regions interacting with HPS4 caused instability of HPS1. These observations extend our understanding of BLOC-3 assembly and represent an important first step in the identification of domains responsible for the biogenesis of lysosome-related organelles. [Copyright &y& Elsevier]

Abstract: Senior–Løken syndrome (SLS) is an autosomal recessive disease characterized by development of a retinitis pigmentosa (RP)- or Leber congenital amaurosis (LCA)-like retinal dystrophy and a medullary cystic kidney disease, nephronophthisis. Mutations in several genes (called nephrocystins) have been shown to cause SLS. The proteins encoded by these genes are localized in the connecting cilium of photoreceptor cells and in the primary cilium of kidney cells. Nephrocystins are thought to have a role in regulating transport of proteins bound to the outer segment/primary cilium; however, the precise molecular mechanisms are largely undetermined. This review will survey the biochemistry, cell biology and existing animal models for each of the nephrocystins as it relates to photoreceptor biology and pathogenesis of retinal degeneration. [Copyright &y& Elsevier]

Abstract: Isovaleric acidemia (IVA) is an autosomal recessive inborn error of leucine metabolism caused by deficiency of mitochondrial isovaleryl-CoA dehydrogenase (IVD). Accumulation of isovaleryl-CoA derivatives to toxic levels results in clinical symptoms of the disease. Here, we investigate the clinical and molecular features of Arab patients with IVA. Patients from five unrelated families were evaluated clinically and for defects in the IVD gene. Four novel mutations (p.F382fs, p.R392H, p.R395Q and p.E408K) have been identified with p.R395Q occurring in two families. In addition, molecular modeling of the identified missense mutations predicted their damaging effects on the protein and computational analysis of the p.F382fs mutation predicted the disruption of a 3′ splicing site resulting in inactive or unstable gene product. Furthermore, we found an unusual case of a 17 years old female homozygous for the p.R392H mutation with no clinical symptoms. Our results illustrate a heterogeneous mutation spectrum and clinical presentation in the relatively small UAE population. [Copyright &y& Elsevier]

Summary: Distal spinal-muscular atrophy 1 (DSMA1) or spinal-muscular atrophy with respiratory distress type 1 (SMARD1) is a rare neuromuscular disorder resulting from IGHMBP2 mutations. It is an autosomal recessive disease. We present the case of a 1-year-old girl admitted for respiratory failure associated with pneumonia. Right hemidiaphragmic elevation on the chest radiograph and distal retractions suggested the diagnosis of DSMA1. It was confirmed by muscle biopsy and molecular analysis. This unrecognized diagnosis should be considered when respiratory failure develops in the first year of life and is associated with diaphragmatic paralysis and distal muscle atrophy. Electromyography with measurement of nerve conduction velocity and muscle biopsy suggest the diagnosis, which must be confirmed by genetic analysis. After identifying the mutations, it is possible to perform prenatal diagnosis. [Copyright &y& Elsevier]

Background and Aims: Distal renal tubular acidosis (dRTA) is characterized by a reduced ability to acidify urine, variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. Mutations in the SLC4A1 gene have been found to cause either autosomal dominant (AD) or autosomal recessive (AR) dRTA. Methods: Four affected individuals and nine healthy family members from two unrelated Chinese families with dRTA were clinically studied. The SLC4A1 gene was screened and analyzed, and the mutations were confirmed using molecular genetic techniques. Results: In family1, the affected individuals had novel compound heterozygous SLC4A1 G494S/G701D mutations inherited from their clinically normal heterozygous father and mother, respectively. In family 2, the affected individuals exhibited a novel 3-bp duplication (c.2715_2717dupCGA) in exon 20 of SLC4A1 that led to the D905dup mutation. The age of presentation was younger, hypokalemia was more severe, and growth retardation was more severe in recessive patients in family 1 than patients with AD dRTA in family 2. Conclusions: This is the first report of dRTA patients with compound heterozygous conditions in mainland China. Two novel SLC4A1 mutations (G494S and D905dup) were identified. Our results confirm the importance of the C-terminal residues of the SLC4A1 gene product in normal acidification processes and indicate that mutations in this region are likely to result in AD dRTA. Our study extends the mutation spectrum of dRTA and is helpful in early molecular diagnoses of dRTA. [ABSTRACT FROM AUTHOR]

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The article offers information related to the Neonatal Sclerosing Cholangitis (NSC) is a rare and severe biliary disease affecting new-borns, and is characterized by jaundice, cholestasis and pale stools. It is noted that liver histology reveal ductular proliferation and bile duct dilatation progresses to biliary cirrhosis and identify homozygous or compound heterozygous mutations in genes inherited in autosomal recessive mode.

Background: Epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha) and their receptor, EGFR, play key roles in polycystic kidney disease (PKD) pathogenesis. Renal expression of two related growth factors, amphiregulin and heparin-binding EGF, has not been examined previously in PKD. The aims of this study of murine autosomal-recessive polycystic kidney disease (ARPKD) were (1) to characterize amphiregulin and heparin-binding EGF expression in cystic versus normal kidneys and cells; and (2) to identify the functional effects of abnormal EGF-related growth factor expression.Methods: Amphiregulin and heparin-binding-EGF expression were examined by immunohistology and Western blot of kidneys and conditionally-immortalized collecting tubule cells obtained from cystic bpk mice (a murine model of ARPKD) and normal littermates. EGF, TGF-alpha, amphiregulin, and heparin-binding EGF in vitro effects on cystic and control collecting tubule cells were assessed by cell proliferation, cyst fluid mitogenicity, and EGFR activation.Results: By immunohistology, amphiregulin and heparin-binding EGF localized to apical and basolateral surfaces of proximal tubule cysts > normal proximal tubules. In cystic collecting tubules, heparin-binding EGF (but not amphiregulin) localized to both apical and basolateral surfaces; whereas in normal collecting tubules, amphiregulin and heparin-binding EGF localized to the basolateral surface only. Increased amphiregulin and heparin-binding EGF expression by Western blot was seen in cystic vs. normal kidneys and increased heparin-binding EGF (but not amphiregulin) expression was present in cystic collecting tubule cell lines vs. controls. EGF, TGF-alpha, amphiregulin, and heparin-binding EGF were all mitogenic to cystic > control collecting tubule cells. Immunoprecipitation of EGF and TGF-alpha reduced cyst fluid mitogenicity by almost 80%, whereas heparin-binding EGF and amphiregulin immunoprecipitations had minimal effects. Differential receptor activation was also seen: Heparin-binding EGF markedly activated EGFR (>EGF = TGF-alpha > amphiregulin), with a greater effect seen in cystic vs. control collecting tubule cells.Conclusion: Multiple EGF-related growth factors are abnormally expressed in murine ARPKD and may have differential roles in disease pathogenesis. In particular, newly identified abnormalities in heparin-binding EGF expression in cystic kidneys and cells may have important implications for disease pathogenesis. [ABSTRACT FROM AUTHOR]

Combination treatment of PKD utilizing dual inhibition of EGF-receptor activity and ligand bioavailability. Background. We have previously demonstrated an essential role for increased epidermal growth factor receptor (EGFR) activity in mediating renal cyst formation and biliary ductal ectasia (BDE) in murine models of autosomal-recessive polycystic kidney disease (ARPKD) such as the BPK mouse. The current study was designed to determine (1 ) if treatment with a second-generation inhibitor of EGFR tyrosine kinase activity, EKB-569, was effective in treatment of ARPKD; (2 ) if tyrosine kinase inhibitor therapy used in combination with pharmacologic reduction of the availability of transforming growth factor-α (TGF-α), using WTACE2, could provide improved therapeutic efficacy and/or decrease potential toxicity; and (3 ) if effectiveness of treatment could be monitored noninvasively in murine ARPKD models by use of serial ultrasonography. Methods. BPK litters were treated with EKB-569 by intraperitoneal injection from postnatal day 7 to postnatal day 21. EKB-569's effectiveness alone or in combination with WTACE2 was measured by reduction in kidney weight/body weight ratios, morphometric renal cystic index, and evaluation of renal function. Renal ultrasound was performed on normal and cystic animals, under different therapeutic regimens, utilizing a 15 mHz linear array transducer, and ultrasound data were compared with histology and renal functional data. Results. Treatment of BPK mice with EKB-569 alone resulted in a marked reduction of kidney weight/body weight ratios, dramatically reduced collecting tubule cystic index, as well as BDE, and improved renal function. The combined treatment with EKB-569 and WTACE2 permitted a 67% reduction in EKB-569 dosage necessary to achieve results equivalent to those produced with EKB-569 alone. Untreated cystic animals died of renal failure, on average, at postnatal day 24 with a collecting tubule cystic index of 4.8, significant BDE, and maximal urine osmolarity of 361 mOsm. Cystic animals treated with EKB-569 and WTACE2 to postnatal day 21 were alive and well with normal renal function, a reduced collecting tubule cystic index of 1.7 (P < 0.02), improvement in BDE, and a threefold increase in maximum urinary concentrating ability (P < 0.01). Renal ultrasound could reliably detect cystic kidneys as early as postnatal day 7 and the natural history as well as effects of therapeutic intervention were clearly delineated by ultrasound evaluation. Conclusion. This study demonstrates that in murine ARPKD (1 ) EKB-569 is as effective as first-generation EGFR tyrosine kinase inhibitors in reducing cyst formation and preserving renal function; (2 ) combination therapy with EKB-569 and WTACE2 provides maximum efficacy in improving renal and biliary abnormalities, at lower doses, thereby minimizing potential toxicity; and (3 ) renal ultrasound provides a simple, reliable, noninvasive method of following natural history and effect of treatment regimens. [ABSTRACT FROM AUTHOR]

Abstract: Hyperostosis–hyperphosphataemia syndrome (HHS) is a rare autosomal recessive metabolic disorder, characterized by recurrent painful swelling of long bones, periosteal new bone formation and cortical hyperostosis or intramedullary sclerosis, hyperphosphatemia and low intact fibroblast growth factor 23 (FGF23) protein levels. It is caused by mutations in 2 genes, N-acetylgalactosaminyltransferase 3 (GalNAc-transferase; GALNT3) and FGF23. We have performed mutation analysis of the GALNT3 and FGF23 genes in a patient with HHS and detected a homozygous mutation in exon 3 of FGF23 gene (NM_020638.2: c.471C>A) which results in amino acid change from phenylalanine 157 to leucin (p.F157L) in receptor interaction site. [Copyright &y& Elsevier]

The development of a polycystic liver is a characteristic of the monogenic disorders: autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), and autosomal dominant polycystic liver disease (ADPLD). Respectively two and one genes mainly cause ADPKD and ARPKD. In contrast, ADPLD is caused by at least six different genes which combined do not even explain the disease development in over half of the ADPLD population. Genetic testing is mainly performed to confirm the likelihood of developing PKD and if renal therapy is essential. However, pure ADPLD patients are frequently not genetically screened as knowledge about the genotype-phenotype correlation is currently limited. This paper will clarify the essence of genetic testing in ADPLD patients. [ABSTRACT FROM AUTHOR]