TRIO loss of function is associated with mild intellectual disability and affects dendritic branching and synapse function
Recently, we marked TRIO for the first time as a candidate gene for intellectual disability (ID). Across diverse vertebrate species, TRIO is a well-conserved Rho GTPase regulator that is highly expressed in the developing brain. However, little is known about the specific events regulated by TRIO during brain development and its clinical impact in humans when mutated. Routine clinical diagnostic testing identified an intragenic de novo deletion of TRIO in a boy with ID. Targeted sequencing of this gene in over 2300 individuals with ID, identified three additional truncating mutations. All index cases had mild to borderline...
Source: Human Molecular Genetics - February 15, 2016 Category: Genetics & Stem Cells Authors: Ba, W., Yan, Y., Reijnders, M. R. F., Schuurs-Hoeijmakers, J. H. M., Feenstra, I., Bongers, E. M. H. F., Bosch, D. G. M., De Leeuw, N., Pfundt, R., Gilissen, C., De Vries, P. F., Veltman, J. A., Hoischen, A., Mefford, H. C., Eichler, E. E., Vissers, L. E. Tags: ARTICLES Source Type: research
Homozygous mutation of PLCZ1 leads to defective human oocyte activation and infertility that is not rescued by the WW-binding protein PAWP
In mammals, sperm–oocyte fusion initiates Ca2+ oscillations leading to a series of events called oocyte activation, which is the first stage of embryo development. Ca2+ signaling is elicited by the delivery of an oocyte-activating factor by the sperm. A sperm-specific phospholipase C (PLCZ1) has emerged as the likely candidate to induce oocyte activation. Recently, PAWP, a sperm-born tryptophan domain-binding protein coded by WBP2NL, was proposed to serve the same purpose. Here, we studied two infertile brothers exhibiting normal sperm morphology but complete fertilization failure after intracytoplasmic sperm injecti...
Source: Human Molecular Genetics - February 15, 2016 Category: Genetics & Stem Cells Authors: Escoffier, J., Lee, H. C., Yassine, S., Zouari, R., Martinez, G., Karaouzene, T., Coutton, C., Kherraf, Z.-e., Halouani, L., Triki, C., Nef, S., Thierry-Mieg, N., Savinov, S. N., Fissore, R., Ray, P. F., Arnoult, C. Tags: ARTICLES Source Type: research
Analysis of the ACTN3 heterozygous genotype suggests that {alpha}-actinin-3 controls sarcomeric composition and muscle function in a dose-dependent fashion
A common null polymorphism (R577X) in ACTN3 causes α-actinin-3 deficiency in ~18% of the global population. There is no associated disease phenotype, but α-actinin-3 deficiency is detrimental to sprint and power performance in both elite athletes and the general population. However, despite considerable investigation to date, the functional consequences of heterozygosity for ACTN3 are unclear. A subset of studies have shown an intermediate phenotype in 577RX individuals, suggesting dose-dependency of α-actinin-3, while others have shown no difference between 577RR and RX genotypes. Here, we investigate th...
Source: Human Molecular Genetics - February 15, 2016 Category: Genetics & Stem Cells Authors: Hogarth, M. W., Garton, F. C., Houweling, P. J., Tukiainen, T., Lek, M., Macarthur, D. G., Seto, J. T., Quinlan, K. G. R., Yang, N., Head, S. I., North, K. N. Tags: ARTICLES Source Type: research
HSAN1 mutations in serine palmitoyltransferase reveal a close structure-function-phenotype relationship
In conclusion, we showed that HSAN1 mutations in SPT have distinct biochemical properties, which allowed for the prediction of the clinical symptoms on the basis of the plasma sphingoid base profile. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - February 15, 2016 Category: Genetics & Stem Cells Authors: Bode, H., Bourquin, F., Suriyanarayanan, S., Wei, Y., Alecu, I., Othman, A., Von Eckardstein, A., Hornemann, T. Tags: ARTICLES Source Type: research
Early-onset sleep defects in Drosophila models of Huntington's disease reflect alterations of PKA/CREB signaling
Huntington's disease (HD) is a progressive neurological disorder whose non-motor symptoms include sleep disturbances. Whether sleep and activity abnormalities are primary molecular disruptions of mutant Huntingtin (mutHtt) expression or result from neurodegeneration is unclear. Here, we report Drosophila models of HD exhibit sleep and activity disruptions very early in adulthood, as soon as sleep patterns have developed. Pan-neuronal expression of full-length or N-terminally truncated mutHtt recapitulates sleep phenotypes of HD patients: impaired sleep initiation, fragmented and diminished sleep, and nighttime hyperactivit...
Source: Human Molecular Genetics - February 15, 2016 Category: Genetics & Stem Cells Authors: Gonzales, E. D., Tanenhaus, A. K., Zhang, J., Chaffee, R. P., Yin, J. C. P. Tags: ARTICLES Source Type: research
Contents Page
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - February 15, 2016 Category: Genetics & Stem Cells Tags: FRONT-MATTER/BACK-MATTER Source Type: research
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(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - February 15, 2016 Category: Genetics & Stem Cells Tags: FRONT-MATTER/BACK-MATTER Source Type: research
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(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - February 15, 2016 Category: Genetics & Stem Cells Tags: FRONT-MATTER/BACK-MATTER Source Type: research
Editorial Board
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - February 15, 2016 Category: Genetics & Stem Cells Tags: FRONT-MATTER/BACK-MATTER Source Type: research
Chronic gastroesophageal reflux disease shares genetic background with esophageal adenocarcinoma and Barrett's esophagus
This study used the linkage disequilibrium (LD) score regression and genomic profile risk scoring approaches to investigate the contribution of multiple common single-nucleotide polymorphisms (SNPs) to the risk of GERD, and the extent of genetic overlap between GERD and BE or EA. Using LD score regression, we estimated an overall phenotypic variance of 7% (95% CI 3–11%) for GERD explained by all the genotyped SNPs. A genetic correlation of 77% (s.e. = 24%, P = 0.0012) between GERD and BE and 88% between GERD and EA (s.e. = 25%, P = 0.0004) was estimated using the LD score regression approach. Results from the genomic...
Source: Human Molecular Genetics - February 5, 2016 Category: Genetics & Stem Cells Authors: Gharahkhani, P., Tung, J., Hinds, D., Mishra, A., Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), Vaughan, T. L., Whiteman, D. C., MacGregor, S., on behalf of the BEACON study investigators Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
Genome-wide DNA methylation study identifies genes associated with the cardiovascular biomarker GDF-15
This study shows that GDF-15 levels are associated with differences in DNA methylation in blood cells, and a subset of the loci are also differentially methylated in participants with MI. However, there might be interactions between GDF-15 levels and methylation in other tissues not addressed in this study. These results provide novel links between GDF-15 and cardiovascular disease. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - February 5, 2016 Category: Genetics & Stem Cells Authors: Ek, W. E., Hedman, A. K., Enroth, S., Morris, A. P., Lindgren, C. M., Mahajan, A., Gustafsson, S., Gyllensten, U., Lind, L., Johansson, A. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
Genome-wide association study of dental caries in the Hispanic Communities Health Study/Study of Latinos (HCHS/SOL)
In conclusion, this was the largest GWAS of dental caries, to date and was the first to target Hispanic/Latino populations. Understanding the factors influencing dental caries susceptibility may lead to improvements in prediction, prevention and disease management, which may ultimately reduce the disparities in oral health across racial, ethnic and socioeconomic strata. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - February 5, 2016 Category: Genetics & Stem Cells Authors: Morrison, J., Laurie, C. C., Marazita, M. L., Sanders, A. E., Offenbacher, S., Salazar, C. R., Conomos, M. P., Thornton, T., Jain, D., Laurie, C. A., Kerr, K. F., Papanicolaou, G., Taylor, K., Kaste, L. M., Beck, J. D., Shaffer, J. R. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
PARK2 enhancement is able to compensate mitophagy alterations found in sporadic Alzheimer's disease
Mitochondrial anomalies have been previously reported in patients' brain and peripheral tissue, suggesting their relevance in sporadic Alzheimer's disease (AD). The present work evaluates mitochondrial function and recycling in human fibroblasts and brain biopsies. Functional studies using patients' skin fibroblasts showed slower mitochondrial membrane potential recovery after a mitochondrial insult together with alterations in lysosomes and autophagy, accompanied by an increase of oxidized and ubiquitinated proteins. Impairment in mitophagy has been proven in these cells due to diminished PARK2 and insufficient vesicle in...
Source: Human Molecular Genetics - February 5, 2016 Category: Genetics & Stem Cells Authors: Martin-Maestro, P., Gargini, R., Perry, G., Avila, J., Garcia-Escudero, V. Tags: ARTICLES Source Type: research
Lysosomal dysfunction and impaired autophagy in a novel mouse model deficient for the lysosomal membrane protein Cln7
CLN7 disease is an autosomal recessive, childhood-onset neurodegenerative lysosomal storage disorder caused by the defective lysosomal membrane protein CLN7. We have disrupted the Cln7/Mfsd8 gene in mice by targeted deletion of exon 2 generating a novel knockout (KO) mouse model for CLN7 disease, which recapitulates key features of human CLN7 disease pathology. Cln7 KO mice showed increased mortality and a neurological phenotype including hind limb clasping and myoclonus. Lysosomal dysfunction in the brain of mutant mice was shown by the storage of autofluorescent lipofuscin-like lipopigments, subunit c of mitochondrial AT...
Source: Human Molecular Genetics - February 5, 2016 Category: Genetics & Stem Cells Authors: Brandenstein, L., Schweizer, M., Sedlacik, J., Fiehler, J., Storch, S. Tags: ARTICLES Source Type: research
Irf6 directly regulates Klf17 in zebrafish periderm and Klf4 in murine oral epithelium, and dominant-negative KLF4 variants are present in patients with cleft lip and palate
Non-syndromic (NS) cleft lip with or without cleft palate (CL/P) is a common disorder with a strong genetic underpinning. Genome-wide association studies have detected common variants associated with this disorder, but a large portion of the genetic risk for NSCL/P is conferred by unidentified rare sequence variants. Mutations in IRF6 (Interferon Regulatory Factor 6) and GRHL3 (Grainyhead-like 3) cause Van der Woude syndrome, which includes CL/P. Both genes encode members of a regulatory network governing periderm differentiation in model organisms. Here, we report that Krüppel-like factor 17 (Klf17), like Grhl3, a...
Source: Human Molecular Genetics - February 5, 2016 Category: Genetics & Stem Cells Authors: Liu, H., Leslie, E. J., Jia, Z., Smith, T., Eshete, M., Butali, A., Dunnwald, M., Murray, J., Cornell, R. A. Tags: ARTICLES Source Type: research
