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Hum Mutat [journal]
- Single Nucleotide Differences (SNDs) Continue to Contaminate the dbSNP Database With Consequences For Human Genomics and Health. [JOURNAL ARTICLE]
- Hum Mutat 2014 Nov 25.
It has been established that up to 8.3% of the biallelic coding SNPs present in dbSNP are actually artefactual polymorphism-like errors, previously termed Single Nucleotide Differences, or SNDs. In this study, a previous analysis of SNPs in dbSNP was extended and updated to examine how the incidence of SNDs has changed over an intervening five year period. The incidence of SNDs was found to be lower than in the previous analysis at 2.2% of all biallelic SNPs. There was only a modest reduction in the percentage of SNDs in the original set of biallelic coding SNPs tested. This suggests that the overall reduction in the incidence of SNDs over the intervening 5-year period is related to an improvement in SNP detection methods and more rigorous curation, rather than efforts to ameliorate the presence of SNDs. We note that SNDs contaminating the dbSNP may lead to erroneous conclusions on human conditions. This article is protected by copyright. All rights reserved.
- The Fragile X Mouse is Cured, Now for the Patients. [Journal Article]
- Hum Mutat 2014 Dec; 35(12):v.
- Cholesterol and cognition: a question of balance? [Journal Article]
- Hum Mutat 2014 Dec; 35(12):v.
- Contents. [Journal Article]
- Hum Mutat 2014 Dec; 35(12):i-iii.
- High-Resolution Breakpoint Analysis Provides Evidence for the Sequence-Directed Nature of Genome Rearrangements in Hereditary Disorders. [JOURNAL ARTICLE]
- Hum Mutat 2014 Nov 24.
Whilst most of the pertinent data on the sequence-directed processes leading to genome rearrangements (GRs) have come from studies on somatic tissues, little is known about GRs in the germ line of patients with hereditary disorders. This study aims at identifying DNA motifs and higher-order structures of genome architecture, which can result in losses and gains of genetic material in the germ line. We first identified candidate motifs by studying 112 pathogenic germ-line genome rearrangements in hereditary colorectal cancer patients, and subsequently created an algorithm, termed recombination type ratio, which correctly predicts the propensity of rearrangements with respect to homologous versus non-homologous recombination events. This article is protected by copyright. All rights reserved.
- Identification and Functional Analysis of a SLC33A1: c.339T>G (p.Ser113Arg) Variant in the Original SPG42 Family. [JOURNAL ARTICLE]
- Hum Mutat 2014 Nov 17.
Using whole exome sequencing, we surveyed all the potential pathogenic variants in an SPG42 family and found five SNPs and four indels that are shared by two patients and lie in the mapped region. Two variants, SLC33A1 p.Ser113Arg and VEPH1 p.Gln433His, co-segregated with the disease. However, VEPH1 p.Gln433His was predicted to be tolerated, thus leaving SLC33A1 p.Ser113Arg as the most plausible causal variant in this family. We found that the phosphorylated SMAD1/5/8 (P-SMAD1/5/8) and BMP receptor type 1A (BMPR1A) were substantially upregulated in fibroblasts derived from an SPG42 individual. Slc33a1 knockdown zebrafish, which exhibited defects in morphology and axon outgrowth, also showed a significant elevation in the level of P-smad1/5/8. While the phenotypes in slc33a1 knockdown zebrafish could be rescued by human wild-type SLC33A1 mRNA, this rescuing effect was diminished by co-injected mutant mRNA encoding p.Ser113Arg, indicating that p.Ser113Arg variant acts in a dominant-negative manner. Importantly, pharmacological blockade of BMPR1 activity by dorsomorphin could efficiently rescue the phenotypic defects in slc33a1 knockdown zebrafish. These results indicate that SLC33A1 can negatively regulate BMP signaling. This article is protected by copyright. All rights reserved.
- Identification and in vivo functional characterization of novel compound heterozygous BMP1 variants in osteogenesis imperfecta. [JOURNAL ARTICLE]
- Hum Mutat 2014 Nov 17.
Osteogenesis imperfecta (OI) comprises a heterogeneous group of disorders that are characterized by susceptibility to bone fractures, and range in severity from a subtle increase in fracture frequency to death in the perinatal period. Most patients have defects in type I collagen biosynthesis with autosomal dominant inheritance; but, many autosomal recessive genes have been reported. We applied whole exome sequencing to identify mutations in a Korean OI patient who had an umbilical hernia, frequent fractures, a markedly short stature, delayed motor development, scoliosis, and dislocation of the radial head, with a bowed radius and ulna. We identified two novel variants in the BMP1 gene: c.808A>G and c.1297G>T. The former variant caused a missense change p.(Met270Val) and the latter variant caused the skipping of exon 10. The hypo-functional nature of the two variants was demonstrated in a zebrafish assay. This article is protected by copyright. All rights reserved.
- ECHS1 Mutations Cause Combined Respiratory Chain Deficiency Resulting in Leigh Syndrome. [JOURNAL ARTICLE]
- Hum Mutat 2014 Nov 13.
The human ECHS1 gene encodes the short chain enoyl coenzyme A (CoA) hydratase, the enzyme that catalyzes the second step of β-oxidation of fatty acids in the mitochondrial matrix. We report on a 21-month-old boy with ECHS1 deficiency resulting in Leigh syndrome. The patient presented with hypotonia, metabolic acidosis, and developmental delay. A combined respiratory chain deficiency was also observed. Targeted exome sequencing of 776 mitochondria-associated genes encoded by nuclear DNA identified compound heterozygous mutations in ECHS1. ECHS1 protein expression was severely depleted in the patient's skeletal muscle and patient-derived myoblasts; a marked decrease of enzyme activity was also evident in patient-derived myoblasts. Immortalized patient-derived myoblasts that expressed exogenous wild-type ECHS1 exhibited the recovery of the ECHS1 activity, indicating that the gene defect was pathogenic. Mitochondrial respiratory complex activity was also mostly restored in these cells, suggesting that there was an unidentified link between deficiency of ECHS1 and respiratory chain. Here we describe the patient with ECHS1 deficiency; these findings will advance our understanding not only the pathology of mitochondrial fatty acid β-oxidation disorders, but also the regulation of mitochondrial metabolism. This article is protected by copyright. All rights reserved.
- Two Siblings with Homozygous Pathogenic Splice Site Variant in Mitochondrial Asparaginyl-tRNA Synthetase (NARS2). [JOURNAL ARTICLE]
- Hum Mutat 2014 Nov 11.
A homozygous missense mutation (c.822G>C) was found in the gene encoding the mitochondrial asparaginyl-tRNA synthetase (NARS2) in two siblings born to consanguineous parents. These siblings presented with different phenotypes: one had mild intellectual disability and epilepsy in childhood whereas the other had severe myopathy. Biochemical analysis of the oxidative phosphorylation (OXPHOS) complexes in both siblings revealed a combined complex I and IV deficiency in skeletal muscle. In-gel activity staining after BN-PAGE confirmed the decreased activity of complex I and IV, and, in addition, showed the presence of complex V subcomplexes. Considering the consanguineous descent, homozygosity mapping and whole exome sequencing were combined revealing the presence of one single missense mutation in the shared homozygous region. The c.822G>C variant affects the 3' splice site of exon 7, leading to skipping of the whole exon 7 and a part of exon 8 in the NARS2 mRNA. In EBV-transformed lymphoblasts a specific decrease in the amount of charged mt-tRNA(Asn) was demonstrated as compared to controls. This confirmed the pathogenic nature of the variant. To conclude, the reported variant in NARS2 results in a combined OXPHOS complex deficiency involving complex I and IV, making NARS2 a new member of disease associated aaRS2. This article is protected by copyright. All rights reserved.
- Varisnp, A Benchmark Database For Variations from dbSNP. [JOURNAL ARTICLE]
- Hum Mutat 2014 Nov 11.
For development and evaluation of methods for predicting the effects of variations, benchmark datasets are needed. Some previously developed datasets are available for this purpose, but newer and larger benchmark sets for benign variants have largely been missing. VariSNP datasets are selected from dbSNP. These subsets were filtered against disease-related variants in the ClinVar, UniProtKB/Swiss-Prot and PhenCode databases, to identify neutral or non-pathogenic cases. All variant descriptions include mapping to reference sequences on chromosomal, genomic, coding DNA and protein levels. The datasets will be updated with automated scripts on a regular basis and are freely available at https://structure.bmc.lu.se/VariSNP. This article is protected by copyright. All rights reserved.