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Human Mutation

Ken Natsuga, Wataru Nishie, Machiko Nishimura, Satoru Shinkuma, Mika Watanabe, Kentaro Izumi, Hideki Nakamura, Yoshiaki Hirako, Hiroshi Shimizu
Plectin is a linker protein that interacts with intermediate filaments and β4 integrin in hemidesmosomes of the epidermal basement membrane zone (BMZ). Type XVII collagen (COL17) has been suggested as another candidate plectin binding partner in hemidesmosomes. Here, we demonstrate that plectin-COL17 binding helps to maintain epidermal BMZ organization. We identified an epidermolysis bullosa (EB) simplex patient as having markedly diminished expression of plectin and COL17 in skin. The patient is compound heterozygous for sequence variants in the plectin gene ( PLEC); one is a truncation and the other is a small in-frame deletion sequence variant...
September 23, 2017: Human Mutation
Li Chen, Philip J Jensik, Joseph T Alaimo, Magdalena Walkiewicz, Seth Berger, Elizabeth Roeder, Eissa A Faqeih, Jonathan A Bernstein, Ann C M Smith, Sureni V Mullegama, David W Saffen, Sarah H Elsea
Deformed epidermal autoregulatory factor-1 (DEAF1), a transcription factor essential for central nervous system and early embryonic development, has recently been implicated in a series of intellectual disability-related neurodevelopmental anomalies termed, in this study, as DEAF1-associated neurodevelopmental disorder (DAND). We identified six potentially deleterious DEAF1 variants in a cohort of individuals with DAND via clinical exome sequencing (CES) and in silico analysis, including two novel de novo variants: missense variant c...
September 22, 2017: Human Mutation
Ayman W El-Hattab, Hongzheng Dai, Mohammed Almannai, Julia Wang, Eissa A Faqeih, Ali Al Asmari, Mohammed A M Saleh, Mohammed A O Elamin, Majid Alfadhel, Fowzan S Alkuraya, Mais Hashem, Mazhor S Aldosary, Rawan Almass, Faten B Almutairi, Maysoon Alsagob, Mohammed Al-Owain, Shirin Al-Sharfa, Zuhair N Al-Hassnan, Zuhair Al Rahbeeni, Mohammed A Al-Muhaizea, Nawal Makhseed, Gretchen K Foskett, David A Stevenson, Natalia Gomez-Ospina, Chung Lee, Richard G Boles, Samantha A Schrier Vergano, Saskia B Wortmann, Wolfgang Sperl, Thomas Opladen, Georg F Hoffmann, Maja Hempel, Holger Prokisch, Bader Alhaddad, Johannes A Mayr, Wenyaw Chan, Namik Kaya, Lee-Jun C Wong
F-box and leucine-rich repeat protein 4 (FBXL4) is a mitochondrial protein whose exact function is not yet known. However, cellular studies have suggested that it plays significant roles in mitochondrial bioenergetics, mitochondrial DNA (mtDNA) maintenance, and mitochondrial dynamics. Biallelic pathogenic variants in FBXL4 are associated with an encephalopathic mtDNA maintenance defect syndrome that is a multisystem disease characterized by lactic acidemia, developmental delay, and hypotonia. Other features are feeding difficulties, growth failure, microcephaly, hyperammonemia, seizures, hypertrophic cardiomyopathy, elevated liver transaminases, recurrent infections, variable distinctive facial features, white matter abnormalities and cerebral atrophy found in neuroimaging, combined deficiencies of multiple electron transport complexes, and mtDNA depletion...
September 22, 2017: Human Mutation
Saskia B Wortmann, Sharita Timal, Hanka Venselaar, Liesbeth T Wintjes, Robert Kopajtich, René G Feichtinger, Carla Onnekink, Mareike Mühlmeister, Ulrich Brandt, Jan A Smeitink, Joris A Veltman, Wolfgang Sperl, Dirk Lefeber, Ger Pruijn, Vesna Stojanovic, Peter Freisinger, Francjan V Spronsen, Terry Gj Derks, Hermine E Veenstra-Knol, Johannes A Mayr, Agnes Rötig, Mark Tarnopolsky, Holger Prokisch, Richard J Rodenburg
Mitochondrial protein synthesis involves an intricate interplay between mitochondrial DNA encoded RNAs and nuclear DNA encoded proteins, such as ribosomal proteins and aminoacyl-tRNA synthases. Eukaryotic cells contain 17 mitochondria-specific aminoacyl-tRNA synthases. WARS2 encodes mitochondrial tryptophanyl-tRNA synthase (mtTrpRS), a homodimeric class Ic enzyme (mitochondrial tryptophan-tRNA ligase; EC Here, we report six individuals from five families presenting with either severe neonatal onset lactic acidosis, encephalomyopathy and early death or a later onset, more attenuated course of disease with predominating intellectual disability...
September 14, 2017: Human Mutation
Virginia Barone, Valeria Del Re, Alessandra Gamberucci, Valentina Polverino, Lucia Galli, Daniela Rossi, Elisa Costanzi, Luana Toniolo, Gianna Berti, Alessandro Malandrini, Giulia Ricci, Gabriele Siciliano, Gaetano Vattemi, Giuliano Tomelleri, Enrico Pierantozzi, Simone Spinozzi, Nila Volpi, Rosella Fulceri, Roberto Battistutta, Carlo Reggiani, Vincenzo Sorrentino
Here we report the identification of three novel missense mutations in the calsequestrin-1 (CASQ1) gene in four patients with tubular aggregate myopathy. These CASQ1 mutations affect conserved amino acids in position 44 (p.(Asp44Asn)), 103 (p.(Gly103Asp)) and 385 (p.(Ile385Thr)). Functional studies, based on turbidity and dynamic light scattering measurements at increasing Ca(2+) concentrations, showed a reduced Ca(2+) -dependent aggregation for the CASQ1 protein containing p.Asp44Asn and p.Gly103Asp mutations and a slight increase in Ca(2+) -dependent aggregation for the p...
September 11, 2017: Human Mutation
Ryan H Purcell, Camilo Toro, William A Gahl, Randy A Hall
Mutations in G protein-coupled receptors (GPCRs) that increase constitutive signaling activity can cause human disease. A de novo C-terminal mutation (R1465W) in the adhesion GPCR BAI2 (also known as ADGRB2) was identified in a patient suffering from progressive spastic paraparesis and other neurological symptoms. In vitro studies revealed that this mutation strongly increases the constitutive signaling activity of an N-terminally cleaved form of BAI2, which represents the activated form of the receptor. Further studies dissecting the mechanism(s) underling this effect revealed that wild-type BAI2 primarily couples to Gαz , with the R1465W mutation conferring increased coupling to Gαi ...
September 10, 2017: Human Mutation
Xiao-Long Zhou, Long-Xia He, Li-Jia Yu, Yong Wang, Xi-Jin Wang, En-Duo Wang, Tao Yang
Leukoencephalopathies are a broad class of common neurologic deterioration for which the etiology remain unsolved in many cases. In a Chinese Han family segregated with sensorineural hearing loss and leukoencephalopathy, candidate pathogenic variants were identified by targeted next-generation sequencing of 144 genes associated with deafness and 108 genes with leukoencephalopathy. Novel compound heterozygous mutations p.R477H and p.P505S were identified in KARS, which encodes lysyl-tRNA synthetase (LysRS), as the only candidate causative variants...
September 8, 2017: Human Mutation
Luís Cardoso, Mark Stevenson, Rajesh V Thakker
Parathyroid carcinoma (PC) may occur as part of a complex hereditary syndrome or an isolated (i.e. non-syndromic) non-hereditary (i.e. sporadic) endocrinopathy. Studies of hereditary, and syndromic forms of PC, which include the hyperparathyroidism-jaw tumour syndrome (HPT-JT), multiple endocrine neoplasia types 1 and 2 (MEN1 and MEN2), and familial isolated primary hyperparathyroidism (FIHP), have revealed some genetic mechanisms underlying PC. Thus, cell division cycle 73 (CDC73) germline mutations cause HPT-JT, and CDC73 mutations occur in 70% of sporadic PC, but in only ∼2% of parathyroid adenomas...
September 7, 2017: Human Mutation
Somadri Ghosh, Céline Huber, Quentin Siour, Sergio S Sousa, Michael Wright, Valérie Cormier-Daire, Christophe Erneux
The SH2 domain containing inositol phosphatase 2 (SHIP2) dephosphorylates PI(3,4,5)P3 to generate PI(3,4)P2, a lipid involved in the control of cell migration and adhesion. The INPPL1 gene that encodes SHIP2 has been found to be mutated in several cases of opsismodysplasia (OPS), a rare autosomal recessive chondrodysplasia characterized by growth plate defects and delayed bone maturation. Reported mutations often result in premature stop codons or missense mutations in SHIP2 catalytic domain. SHIP2 biochemical properties are known from studies in cancer cells; its role in endochondral ossification is unknown...
September 4, 2017: Human Mutation
Morten Hillmer, Anna Summerer, Victor-Felix Mautner, Josef Högel, David N Cooper, Hildegard Kehrer-Sawatzki
Precise characterization of NAHR breakpoints is key to identifying those features that influence NAHR frequency. Until now, analysis of NAHR-mediated rearrangements has generally been performed by comparison of the breakpoint-spanning sequences with the human genome reference sequence. We show here that the haplotype diversity of NAHR hotspots may interfere with breakpoint-mapping. We studied the transmitting parents of individuals with germline type-1 NF1 deletions mediated by NAHR within the PRS1 or PRS2 hotspots...
September 1, 2017: Human Mutation
Kelvin C de Andrade, Lisa Mirabello, Douglas R Stewart, Eric Karlins, Roelof Koster, Mingyi Wang, Susan M Gapstur, Mia M Gaudet, Neal D Freedman, Maria T Landi, Nathanaël Lemonnier, Pierre Hainaut, Sharon A Savage, Maria I Achatz
Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer disorder associated with pathogenic germline variants in TP53, with a high penetrance over an individual's lifetime. The actual population prevalence of pathogenic germline TP53 mutations is still unclear. The aim of this study was to estimate the prevalence of potentially pathogenic TP53 exonic variants in three data sources, totaling 63,983 unrelated individuals from three sequencing databases. Potential pathogenicity was defined using an original algorithm combining bioinformatic prediction tools, clinical significance evidences, and functional data...
September 1, 2017: Human Mutation
Yue Zhang, Tiantian Zhou, Yayan Niu, Meiling He, Can Wang, Meng Liu, Junhua Yang, Yonghong Zhang, Jianping Zhou, Koichi Fukuda, Jun Qin, Ningzheng Dong, Qingyu Wu
Corin is a serine protease that activates atrial natriuretic peptide (ANP). CORIN gene variants have been reported in patients with hypertension. To date, however, the prevalence of CORIN variants in hypertensive patients remains unknown. To understand the prevalence and functional significance of CORIN variants in hypertension, we sequenced CORIN exons in 300 normal and 401 hypertensive individuals in a Chinese population and identified nine non-synonymous variants, of which eight were not characterized previously...
August 31, 2017: Human Mutation
Marta Frigeni, Bijina Balakrishnan, Xue Yin, Fernanda R O Calderon, Rong Mao, Marzia Pasquali, Nicola Longo
Primary carnitine deficiency is caused by a defect in the OCTN2 carnitine transporter encoded by the SLC22A5 gene. It can cause hypoketotic hypoglycemia or cardiomyopathy in children, and sudden death in children and adults. Fibroblasts from affected patients have reduced carnitine transport. We evaluated carnitine transport in fibroblasts from 358 subjects referred for possible carnitine deficiency. Carnitine transport was reduced to 20% or less of normal in fibroblasts of 140 out of 358 subjects. Sequencing of the 10 exons and flanking regions of the SLC22A5 gene in 95 out of 140 subjects identified causative variants in 84% of the alleles...
August 25, 2017: Human Mutation
Laurens Wiel, Hanka Venselaar, Joris A Veltman, Gert Vriend, Christian Gilissen
Whole exomes of patients with a genetic disorder are nowadays routinely sequenced but interpretation of the identified genetic variants remains a major challenge. The increased availability of population-based human genetic variation has given rise to measures of genetic tolerance that have been used, for example, to predict disease-causing genes in neurodevelopmental disorders. Here, we investigated whether combining variant information from homologous protein domains can improve variant interpretation. For this purpose, we developed a framework that maps population variation and known pathogenic mutations onto 2,750 "meta-domains...
August 16, 2017: Human Mutation
Manon S Oud, Liliana Ramos, Moira K O'Bryan, Robert I McLachlan, Özlem Okutman, Stephane Viville, Petra F de Vries, Dominique F C M Smeets, Dorien Lugtenberg, Jayne Y Hehir-Kwa, Christian Gilissen, Maartje van de Vorst, Lisenka E L M Vissers, Alexander Hoischen, Aukje M Meijerink, Kathrin Fleischer, Joris A Veltman, Michiel J Noordam
Microdeletions of the Y chromosome (YCMs), Klinefelter syndrome (47,XXY), and CFTR mutations are known genetic causes of severe male infertility, but the majority of cases remain idiopathic. Here, we describe a novel method using single molecule Molecular Inversion Probes (smMIPs), to screen infertile men for mutations and copy number variations affecting known disease genes. We designed a set of 4,525 smMIPs targeting the coding regions of causal (n = 6) and candidate (n = 101) male infertility genes. After extensive validation, we screened 1,112 idiopathic infertile men with non-obstructive azoospermia or severe oligozoospermia...
August 11, 2017: Human Mutation
Anja Kathrin Mayer, Caroline Van Cauwenbergh, Christine Rother, Britta Baumann, Peggy Reuter, Elfride De Baere, Bernd Wissinger, Susanne Kohl
Achromatopsia is a rare autosomal recessive cone disorder characterized by color vision defects, photophobia, nystagmus and severely reduced visual acuity. The disease is caused by mutations in genes encoding crucial components of the cone phototransduction cascade (CNGA3, CNGB3, GNAT2, PDE6C, and PDE6H) or in ATF6, involved in the unfolded protein response. CNGB3 encoding the beta subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors is the major achromatopsia gene. Here, we present a comprehensive spectrum of CNGB3 mutations and their prevalence in a cohort of 1,074 independent families clinically diagnosed with achromatopsia...
August 10, 2017: Human Mutation
Regina Proskorovski-Ohayon, Rotem Kadir, Analia Michalowski, Hagit Flusser, Yonatan Perez, Eli Hershkovitz, Sara Sivan, Ohad S Birk
PAX7 encodes a transcription factor essential in neural crest formation, myogenesis and pituitary lineage specification. Pax7 null mice fail to thrive and exhibit muscle weakness, dying within 3 weeks. We describe a human autosomal recessive syndrome, with failure to thrive, severe global developmental delay, microcephaly, axial hypotonia, pyramidal signs, dystonic postures, seizures, irritability and self-mutilation. Aside from low blood carnitine levels, biochemical and metabolic screen was normal, with growth hormone deficiency in one patient...
August 4, 2017: Human Mutation
Li-Xi Li, Gong-Lu Liu, Zhi-Jun Liu, Cong Lu, Zhi-Ying Wu
Charcot-Marie-Tooth disease type 4D (CMT4D) is an autosomal-recessive demyelinating form of CMT characterized by a severe distal motor and sensory neuropathy. NDRG1 is the causative gene for CMT4D. To date, only four mutations in NDRG1 -c.442C>T (p.Arg148*), c.739delC (p.His247Thrfs*74), c.538-1G>A, and duplication of exons 6-8-have been described in CMT4D patients. Here, using targeted next-generation sequencing examination, we identified for the first time two homozygous missense variants in NDRG1, c...
August 3, 2017: Human Mutation
Yuri Sakaguchi, Tomoko Uehara, Hisato Suzuki, Kenjiro Kosaki, Toshiki Takenouchi
No abstract text is available yet for this article.
August 1, 2017: Human Mutation
Lun-Ching Chang, Suleyman Vural, Dmitriy Sonkin
Tumor-suppressor genes can be inactivated by several mechanisms and, in a majority of cases, both alleles need to be affected. One of the mechanisms of inactivation is due to deletions ranging from dozen to hundreds of nucleotides; such deletions are often missed by variant callers. HomDelDetect is a method to detect such homozygous deletions in cancer models, such as cancer cell lines and potentially patient tumor-derived xenografts. This method can be applied to partial exome, whole-exome sequencing, whole-genome sequencing, and RNA-seq data...
August 1, 2017: Human Mutation
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