Download the Free Unbound MEDLINE PubMed App to your smartphone or tablet.
Available for iPhone, iPad, iPod touch, and Android.
Hum Mutat [journal]
- New Target Genes in Endometrial Tumors Show a Role for the Estrogen-Receptor Pathway in Microsatellite Unstable Cancers. [JOURNAL ARTICLE]
- Hum Mutat 2014 Sep 17.
Microsatellite instability (MSI) in tumors results in an accumulation of mutations in (target) genes. Previous studies suggest that the profile of target genes differs according to tumor-type. This paper describes the first genome-wide search for target genes for mismatch repair deficient endometrial cancers. Genes expressed in normal endometrium containing coding repeats were analyzed for mutations in tumors. We identified 44 possible genes of which seven are highly mutated (>15%). Some candidates were also found mutated in colorectal and gastric tumors. The most frequently mutated gene, NRIP1 encoding nuclear receptor-interacting protein 1, was silenced in an endometrial tumor cell line and expression micro-array experiments were performed. Silencing of NRIP1 was associated with differences in the expression of several genes in the estrogen-receptor (ER) network. Furthermore, an enrichment of genes related to cell cycle (regulation) and replication was observed. We present a new profile of target genes, some of them tissue-specific, while others seem to play a more general role in MSI tumors. The high mutation frequency combined with the expression data suggest, for the first time, an involvement of NRIP1 in endometrial cancer development. This article is protected by copyright. All rights reserved.
- Disruption of the SEMA3D Gene in a Patient with Congenital Heart Defects. [JOURNAL ARTICLE]
- Hum Mutat 2014 Sep 18.
Congenital heart disease (CHD) is the leading malformation among newborns. However, its genetic basis remains mostly unknown. We report a child with transposition of the great arteries, ventricular septal defect and coarctation of the aorta. By array comparative genomic hybridization, we identified a duplication of the 5' half of semaphorin3D (SEMA3D). Breakpoint sequencing and fiber fluorescent in situ hybridization showed tandem duplication. Expression studies showed a higher level of SEMA3D mRNA in patient's lymphoblasts versus controls. Moreover, we demonstrated the presence of a truncated SEMA3D poly-A tailed mRNA, resulting from an abnormal transcription of SEMA3D partial duplication. Sema3D is an axon guidance protein essential for the correct migration of cardiac neural crest cells (CNCC) into the outflow tract. Sema3D(-/-) mice present with CHD but its role in humans remains unclear. Our results suggest that truncated SEMA3D may have hampered the migration of CNCC during heart development, contributing to patient's CHD. This article is protected by copyright. All rights reserved.
- Identification of Pathogenic Mechanisms of COCH Mutations, Abolished Cochlin Secretion and Intracellular Aggregate Formation: Genotype-Phenotype Correlations in DFNA9 Deafness and Vestibular Disorder. [JOURNAL ARTICLE]
- Hum Mutat 2014 Sep 17.
Mutations in COCH cause autosomal dominant non-syndromic hearing loss with variable degrees of clinical onset and vestibular malfunction. We selected eight uncharacterized mutations and performed immunocytochemical and Western blot analyses to track cochlin through the secretory pathway. We then performed a comprehensive analysis of clinical information from DFNA9 patients with all 21 known COCH mutations in conjunction with cellular and molecular findings to identify genotype-phenotype correlations. Our studies revealed that five mutants were not secreted into the media: two vWFA domain mutants, which were not transported from the ER to Golgi complex and formed high-molecular-weight aggregates in cell lysates; and three LCCL domain mutants, which were detected as intracellular dimeric cochlins. Mutant cochlins that were not secreted and accumulated in cells result in earlier age of onset of hearing defects. In addition, individuals with LCCL domain mutations show accompanying vestibular dysfunction, whereas those with vWFA domain mutations exhibit predominantly hearing loss. This is the first report showing failure of mutant cochlin transport through the secretory pathway, abolishment of cochlin secretion, and formation and retention of dimers and large multimeric intracellular aggregates, and high correlation with earlier onset and progression of hearing loss in individuals with these DFNA9-causing mutations. This article is protected by copyright. All rights reserved.
- Identification of Fragile X Syndrome-Specific Molecular Markers in Human Fibroblasts: A Useful Model to Test the Efficacy of Therapeutic Drugs. [JOURNAL ARTICLE]
- Hum Mutat 2014 Sep 16.
Fragile X Syndrome (FXS) is the most frequent cause of inherited intellectual disability and autism. It is caused by the absence of the fragile X mental retardation 1 (FMR1) gene product, FMRP, an RNA-binding protein involved in the regulation of translation of a subset of brain mRNAs. In Fmr1 knockout (KO) mice, the absence of FMRP results in elevated protein synthesis in the brain as well as increased signaling of many translational regulators. Whether protein synthesis is also dysregulated in FXS patients is not firmly established. Here, we demonstrate that fibroblasts from FXS patients have significantly elevated rates of basal protein synthesis along with increased levels of phosphorylated mechanistic target of rapamycin (p-mTOR), phosphorylated extracellular signal regulated kinase 1/2 (p-ERK 1/2) and phosphorylated p70 ribosomal S6 kinase 1 (p-S6K1). Treatment with small molecules that inhibit S6K1, and a known FMRP target, phosphoinositide 3-kinase (P13K) catalytic subunit p110β, lowered the rates of protein synthesis in both control and patient fibroblasts. Our data thus demonstrate that fibroblasts from FXS patients may be a useful in vitro model to test the efficacy and toxicity of potential therapeutics prior to clinical trials, as well as for drug screening and designing personalized treatment approaches. This article is protected by copyright. All rights reserved.
- Nonsense mutation in coiled coil domain containing 151 gene (CCDC151) causes Primary ciliary dyskinesia. [JOURNAL ARTICLE]
- Hum Mutat 2014 Sep 16.
Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder characterised by impaired ciliary function which leads to subsequent clinical phenotypes such as chronic sino-pulmonary disease. PCD is also a genetically heterogeneous disorder with many single gene mutations leading to similar clinical phenotypes. Here we present a novel PCD causal gene, coiled coil domain containing 151 (CCDC151), which has been shown to be essential in motile cilia of many animals and other vertebrates but its effects in humans was not observed until current. We observed a novel nonsense mutation in a homozygous state in the CCDC151 gene (NM_145045.4:c.924C > A:p.(E309*)) in a clinically diagnosed PCD patient from a consanguineous family of Arabic ancestry. The variant was absent in 238 randomly selected individuals indicating that the variant is not a founder mutation. Our finding also shows that given prior knowledge from model organisms, even a single whole-exome sequence can be sufficient to discover a novel causal gene. This article is protected by copyright. All rights reserved.
- Altered GPM6A/M6 Dosage Impairs Cognition and Causes Phenotypes Responsive to Cholesterol in Human and Drosophila. [JOURNAL ARTICLE]
- Hum Mutat 2014 Sep 16.
Glycoprotein M6A (GPM6A) is a neuronal transmembrane protein of the PLP/DM20 (proteolipid protein) family that associates with cholesterol-rich lipid rafts and promotes filopodia formation. We identified a de novo duplication of the GPM6A gene in a patient with learning disability and behavioral anomalies. Expression analysis in blood lymphocytes showed increased GPM6A levels. An increase of patient-derived lymphoblastoid cells carrying membrane protrusions supports a functional effect of this duplication. To study the consequences of GPM6A dosage alterations in an intact nervous system, we employed Drosophila melanogaster as a model organism. We found that knockdown of Drosophila M6, the sole member of the PLP family in flies, in the wing and whole organism causes malformation and lethality, respectively. These phenotypes as well as the protrusions of patient-derived lymphoblastoid cells with increased GPM6A levels can be alleviated by cholesterol supplementation. Notably, overexpression as well as loss of M6 in neurons specifically compromises long-term memory in the courtship conditioning paradigm. Our findings thus indicate a critical role of correct GPM6A/M6 levels for cognitive function and support a role of the GPM6A duplication for the patient's phenotype. Together with other recent findings, this study highlights compromised cholesterol homeostasis as a recurrent feature in cognitive phenotypes. This article is protected by copyright. All rights reserved.
- GNAS Mutations in Pseudohypoparathyroidism Type 1a and Related Disorders. [JOURNAL ARTICLE]
- Hum Mutat 2014 Sep 13.
Pseudohypoparathyroidism type 1a (PHP1a) is characterised by hypocalcaemia and hyperphosphataemia due to parathyroid hormone (PTH) resistance, in association with the features of Albright Hereditary Osteodystrophy (AHO). PHP1a is caused by maternally inherited inactivating mutations of Gs-alpha, which is encoded by a complex imprinted locus termed GNAS. Paternally inherited mutations can lead either to Pseudopseudohypoparathyroidism (PPHP) characterised by AHO alone, or to Progressive Osseous Heteroplasia (POH), characterised by severe heterotopic ossification. The clinical aspects and molecular genetics of PHP1a and its related disorders are reviewed together with the 343 kindreds with Gs-alpha germline mutations reported so far in the literature. These 343 (176 different) mutations are scattered throughout the 13 exons that encode Gs-alpha and consist of 44.9% frameshift, 28.0% missense, 14.0% nonsense, and 9.0% splice-site mutations, 3.2% in-frame deletions or insertions, and 0.9% whole or partial gene deletions. Frameshift and other highly disruptive mutations were more frequent in the reported 37 POH kindreds than in PHP1a/PPHP kindreds (97.3% vs. 68.7%, p<0.0001). This mutation update and respective genotype-phenotype data may be of use for diagnostic and research purposes and contribute to a better understanding of these complex disorders. This article is protected by copyright. All rights reserved.
- Integrated Sequence Analysis Pipeline Provides One-Stop Solution for Identifying Disease-Causing Mutations. [JOURNAL ARTICLE]
- Hum Mutat 2014 Sep 13.
Next-generation sequencing has greatly accelerated the search for disease-causing defects, but even for experts the data analysis can be a major challenge. To facilitate the data processing in a clinical setting, we have developed a novel Medical Re-sequencing Analysis Pipeline (MERAP). MERAP assesses the quality of sequencing, and has optimized capacity for calling variants, including Single Nucleotide Variants, insertions and deletions, Copy Number Variation, and other structural variants. MERAP identifies polymorphic and known causal variants by filtering against public-domain databases, and flags non-synonymous and splice-site changes. MERAP uses a logistic model to estimate the causal likelihood of a given missense variant. MERAP considers the relevant information such as phenotype and interaction with known disease-causing genes. MERAP compares favorably with GATK, one of the widely used tools, because of its higher sensitivity for detecting indels, its easy installation, and its economical use of computational resources. Upon testing more than 1200 individuals with mutations in known and novel disease genes, MERAP proved highly reliable, as illustrated here for 5 families with disease-causing variants. We believe that the clinical implementation of MERAP will expedite the diagnostic process of many disease-causing defects. This article is protected by copyright. All rights reserved.
- Capture of Somatic mtDNA Point Mutations with Severe Effects on Oxidative Phosphorylation in Synaptosome Cybrid Clones from Human Brain. [JOURNAL ARTICLE]
- Hum Mutat 2014 Sep 13.
Mitochondrial DNA (mtDNA) is replicated throughout life in post-mitotic cells, resulting in higher levels of somatic mutation than in nuclear genes. However, controversy remains as to the importance of low-level mtDNA somatic mutants in cancerous and normal human tissues. To capture somatic mtDNA mutations for functional analysis, we generated synaptosome cybrids from synaptic endings isolated from fresh hippocampus and cortex brain biopsies. We analysed the whole mtDNA genome from 120 cybrid clones derived from four individual donors by chemical cleavage of mismatch and Sanger sequencing, scanning around 2 million base pairs. Seventeen different somatic point mutations were identified, including eight coding region mutations, four of which result in frameshifts. Examination of one cybrid clone with a novel m.2949_2953delCTATT mutation in MT-RNR2 (which encodes mitochondrial 16S rRNA) revealed a severe disruption of mtDNA-encoded protein translation. We also performed functional studies on a homoplasmic nonsense mutation in MT-ND1, previously reported in oncocytomas, and show that both ATP generation and the stability of oxidative phosphorylation complex I are disrupted. As the mtDNA remains locked against direct genetic manipulation, we demonstrate that the synaptosome cybrid approach can capture biologically relevant mtDNA mutants in vitro to study effects on mitochondrial respiratory chain function. This article is protected by copyright. All rights reserved.
- Mutation Update for UBE3A Variants in Angelman Syndrome. [JOURNAL ARTICLE]
- Hum Mutat 2014 Sep 11.
Angelman syndrome is a neurodevelopmental disorder caused by a deficiency of the imprinted and maternally expressed UBE3A gene. Although de novo genetic and epigenetic imprinting defects of UBE3A genomic locus account for majority of Angelman diagnoses, approximately 10% of individuals affected with Angelman syndrome are a result of UBE3A loss-of-function mutations occurring on the expressed maternal chromosome. The variants described in this manuscript represent the analysis of 2515 patients referred for UBE3A gene sequencing at our institution, along with a comprehensive review of the UBE3A mutation literature. Of these, 267 (10.62%) patients had a report issued for detection of a UBE3A gene nucleotide variant, which in many cases involved family studies resulting in reclassification of variants of unknown clinical significance (VUS). Overall, 111 (4.41%) probands had a nucleotide change classified as pathogenic or strongly favored to be pathogenic, 29 (1.15%) had a variant of unknown clinical significance, and 126 (5.0%) had a nucleotide change classified as benign or strongly favored to be benign. All variants and their clinical interpretations are submitted to NCBI ClinVar, a freely accessible human variation and phenotype database. This article is protected by copyright. All rights reserved.