Talin1 dysfunction is genetically linked to systemic capillary leak syndrome.

Systemic capillary leak syndrome (SCLS) is a rare life-threatening disorder due to profound vascular leak. The trigger and the cause of the disease is currently unknown and there is no specific treatment. Here, we identified a rare heterozygous splice-site variant in the TLN1 gene in a familial SCLS case, suggestive of autosomal dominant inheritance with incomplete penetrance. Talin1 has a key role in cell adhesions by activating and linking integrins to the actin cytoskeleton. This variant causes in-frame skipping of exon 54 and is predicted to affect talin’s c-terminal actin binding site (ABS3). Modelling the SCLS-TLN1 variant by mimicking the actin-binding disruption in TLN1 heterozygous endothelial cells resulted in disorganized endothelial adherens junctions. Mechanistically, we established that disruption of talin’s ABS3 sequestrates talin’s interacting partner, vinculin, at cell-extracellular matrix adhesions, leading to destabilization of the endothelial barrier. We propose that pathogenic variant in TLN1 underlie SCLS, providing insight into the molecular mechanism of the disease which can be explored for future therapeutic interventions

Molecular genetics of familial hypercholesterolemia in Israel-revisited

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the genes for LDL receptor (LDLR), apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type9 (PCSK9). The purpose of the current investigation was to define the current spectrum of mutations causing FH in Israel. METHODS: New families were collected through the MEDPED (Make Early Diagnosis Prevent Early Death) FH program. Molecular analysis of the LDLR, PCSK9 and APOB genes was done using High Resolution Melt and direct sequencing in 67 index cases. A 6-SNP LDL-C gene score calculation for polygenic hypercholesterolaemia was done using TaqMan genotyping. RESULTS: Mean serum cholesterol was 7.48 ± 1.89 mmol/L and the mean serum LDL-C was 5.99 ± 1.89 mmol/L. Mutations in the LDLR and APOB gene were found in 24 cases (35.8%), with 16 in LDLR, none in PCSK9 and one, p.(R3527Q), in the APOB gene, which is the first APOB mutation carrier identified in the Israeli population. Of the LDLR mutations, two were novel; p.(E140A) and a promoter variant, c.-191C > A. The c.2479G > A p.(V827I) in exon 17 of the LDLR gene was found in 8 patients (33.3% of the mutations) with modestly elevated LDL-C, but also in a compound heterozygous patient with a clinical homozygous FH phenotype, consistent with this being a "mild" FH-causing variant. A significantly higher 6-SNP LDL-C score was found in mutation-negative cases compared with a normal Caucasian cohort (p = 0.03), confirming that polygenic inheritance of common LDL-C raising SNPs can produce an FH phenocopy. CONCLUSIONS: The results indicate a different spectrum of genetic causes of FH from that found previously, in concordance with the heterogeneous and changing origins of the Israeli population, and confirm that a polygenic cause is also contributing to the FH phenotype in Israel

Ashkenazi Jewish Centenarians Do Not Demonstrate Enrichment in Mitochondrial Haplogroup J

BACKGROUND: Association of mitochondrial haplogroup J with longevity has been reported in several population subgroups. While studies from northern Italy and Finland, have described a higher frequency of haplogroup J among centenarians in comparison to non-centenarian, several other studies could not replicate these results and suggested various explanations for the discrepancy. METHODOLOGY/PRINCIPAL FINDINGS: We have evaluated haplogroup frequencies among Ashkenazi Jewish centenarians using two different sets of matched controls. No difference was observed in the haplogroup J frequencies between the centenarians or either matched control group, despite adequate statistical power to detect such a difference. Furthermore, the lack of association was robust to population substructure in the Ashkenazi Jewish population. Given this discrepancy with the previous reported associations in the northern Italian and the Finnish populations, we conducted re-analysis of these previously published data, which supported one of several possible explanations: i) inadequate matching of cases and controls; ii) inadequate adjustment for multiple comparison testing; iii) cryptic population stratification. CONCLUSIONS/SIGNIFICANCE: There does not exist a universal association of mitochondrial haplogroup J with longevity across all population groups. Reported associations in specialized populations may reflect genetic or other interactions specific to those populations or else cryptic confounding influences, such as inadequate matching attributable to population substructure, which are of general relevance to all studies of the possible association of mitochondrial DNA haplogroups with common complex phenotypes

Survival bias and drug interaction can attenuate cross-sectional case-control comparisons of genes with health outcomes. An example of the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism and coronary heart disease

<p>Abstract</p> <p>Background</p> <p>Case-control studies typically exclude fatal endpoints from the case set, which we hypothesize will substantially underestimate risk if survival is genotype-dependent. The loss of fatal cases is particularly nontrivial for studies of coronary heart disease (CHD) because of significantly reduced survival (34% one-year fatality following a coronary attack). A case in point is the <it>KIF6 </it>Trp719Arg polymorphism (rs20455). Whereas six prospective studies have shown that carriers of the <it>KIF6 </it>Trp719Arg risk allele have 20% to 50% greater CHD risk than non-carriers, several cross-sectional case-control studies failed to show that carrier status is related to CHD. Computer simulations were therefore employed to assess the impact of the loss of fatal events on gene associations in cross-sectional case-control studies, using <it>KIF6 </it>Trp719Arg as an example.</p> <p>Results</p> <p>Ten replicates of 1,000,000 observations each were generated reflecting Canadian demographics. Cardiovascular disease (CVD) risks were assigned by the Framingham equation and events distributed among <it>KIF6 </it>Trp719Arg genotypes according to published prospective studies. Logistic regression analysis was used to estimate odds ratios between <it>KIF6 </it>genotypes. Results were examined for 33%, 41.5%, and 50% fatality rates for incident CVD.</p> <p>In the absence of any difference in percent fatalities between genotypes, the odds ratios (carriers vs. noncarriers) were unaffected by survival bias, otherwise the odds ratios were increasingly attenuated as the disparity between fatality rates increased between genotypes. Additional simulations demonstrated that statin usage, shown in four clinical trials to substantially reduce the excess CHD risk in the <it>KIF6 </it>719Arg variant, should also attenuate the <it>KIF6 </it>719Arg odds ratio in case-control studies.</p> <p>Conclusions</p> <p>These computer simulations show that exclusions of prior CHD fatalities attenuate odds ratios of case-control studies in proportion to the difference in the percent fatalities between genotypes. Disproportionate CHD survival for <it>KIF6 </it>Trip719Arg carriers is suggested by their 50% greater risk for recurrent myocardial infarction. This, and the attenuation of <it>KIF6 </it>719Arg carrier risk with statin use, may explain the genotype's weak association with CHD in cross-sectional case-control studies. The results may be relevant to the underestimation of risk in cross-sectional case-control studies of other genetic CHD-risk factors affecting survival.</p

Homozygous frameshift mutations in FAT1 cause a syndrome characterized by colobomatous-microphthalmia, ptosis, nephropathy and syndactyly

A failure in optic fissure fusion during development can lead to blinding malformations of the eye. Here, we report a syndrome characterized by facial dysmorphism, colobomatous microphthalmia, ptosis and syndactyly with or without nephropathy, associated with homozygous frameshift mutations in FAT1. We show that Fat1 knockout mice and zebrafish embryos homozygous for truncating fat1a mutations exhibit completely penetrant coloboma, recapitulating the most consistent developmental defect observed in affected individuals. In human retinal pigment epithelium (RPE) cells, the primary site for the fusion of optic fissure margins, FAT1 is localized at earliest cell-cell junctions, consistent with a role in facilitating optic fissure fusion during vertebrate eye development. Our findings establish FAT1 as a gene with pleiotropic effects in human, in that frameshift mutations cause a severe multi-system disorder whereas recessive missense mutations had been previously associated with isolated glomerulotubular nephropathy

De novo mutations in GRIN1 cause extensive bilateral polymicrogyria

Polymicrogyria is a malformation of cortical development. The aetiology of polymicrogyria remains poorly understood. Using whole-exome sequencing we found de novo heterozygous missense GRIN1 mutations in 2 of 57 parent-offspring trios with polymicrogyria. We found nine further de novo missense GRIN1 mutations in additional cortical malformation patients. Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy. GRIN1 encodes GluN1, the essential subunit of the N-methyl-d-aspartate receptor. The polymicrogyria-associated GRIN1 mutations tended to cluster in the S2 region (part of the ligand-binding domain of GluN1) or the adjacent M3 helix. These regions are rarely mutated in the normal population or in GRIN1 patients without polymicrogyria. Using two-electrode and whole-cell voltage-clamp analysis, we showed that the polymicrogyria-associated GRIN1 mutations significantly alter the in vitro activity of the receptor. Three of the mutations increased agonist potency while one reduced proton inhibition of the receptor. These results are striking because previous GRIN1 mutations have generally caused loss of function, and because N-methyl-d-aspartate receptor agonists have been used for many years to generate animal models of polymicrogyria. Overall, our results expand the phenotypic spectrum associated with GRIN1 mutations and highlight the important role of N-methyl-d-aspartate receptor signalling in the pathogenesis of polymicrogyria

Autosomal recessive cerebellar ataxias

Autosomal recessive cerebellar ataxias (ARCA) are a heterogeneous group of rare neurological disorders involving both central and peripheral nervous system, and in some case other systems and organs, and characterized by degeneration or abnormal development of cerebellum and spinal cord, autosomal recessive inheritance and, in most cases, early onset occurring before the age of 20 years. This group encompasses a large number of rare diseases, the most frequent in Caucasian population being Friedreich ataxia (estimated prevalence 2–4/100,000), ataxia-telangiectasia (1–2.5/100,000) and early onset cerebellar ataxia with retained tendon reflexes (1/100,000). Other forms ARCA are much less common. Based on clinicogenetic criteria, five main types ARCA can be distinguished: congenital ataxias (developmental disorder), ataxias associated with metabolic disorders, ataxias with a DNA repair defect, degenerative ataxias, and ataxia associated with other features. These diseases are due to mutations in specific genes, some of which have been identified, such as frataxin in Friedreich ataxia, α-tocopherol transfer protein in ataxia with vitamin E deficiency (AVED), aprataxin in ataxia with oculomotor apraxia (AOA1), and senataxin in ataxia with oculomotor apraxia (AOA2). Clinical diagnosis is confirmed by ancillary tests such as neuroimaging (magnetic resonance imaging, scanning), electrophysiological examination, and mutation analysis when the causative gene is identified. Correct clinical and genetic diagnosis is important for appropriate genetic counseling and prognosis and, in some instances, pharmacological treatment. Due to autosomal recessive inheritance, previous familial history of affected individuals is unlikely. For most ARCA there is no specific drug treatment except for coenzyme Q10 deficiency and abetalipoproteinemia

Biallelic variants in the ectonucleotidase ENTPD1 cause a complex neurodevelopmental disorder with intellectual disability, distinct white matter abnormalities, and spastic paraplegia.

OBJECTIVE: Human genomics established that pathogenic variation in diverse genes can underlie a single disorder. For example, hereditary spastic paraplegia (HSP) is associated with over 80 genes with frequently only few affected individuals described for each gene. Herein, we characterize a large cohort of individuals with biallelic variation in ENTPD1, a gene previously linked to spastic paraplegia 64 (MIM# 615683). METHODS: Individuals with biallelic ENTPD1 variants were recruited worldwide. Deep phenotyping and molecular characterizations were performed. RESULTS: A total of 27 individuals from 17 unrelated families were studied; additional phenotypic information was collected from published cases. Twelve novel pathogenic ENTPD1 variants are described: c.398_399delinsAA; p.(Gly133Glu), c.540del; p.(Thr181Leufs* 18), c.640del; p.(Gly216Glufs* 75), c.185T>G; p.(Leu62*), c.1531T>C; p.(*511Glnext* 100), c.967C>T; p.(Gln323*), c.414-2_414-1del, and c.146 A>G; p.(Tyr49Cys) including four recurrent variants c.1109T>A; p.(Leu370* ), c.574-6_574-3del, c.770_771del; p.(Gly257Glufs*18), and c.1041del; p.(Ile348Phefs*19). Shared disease traits include: childhood-onset, progressive spastic paraplegia, intellectual disability (ID), dysarthria, and white matter abnormalities. In vitro assays demonstrate that ENTPD1 expression and function are impaired and that c.574-6_574-3del causes exon skipping. Global metabolomics demonstrates ENTPD1 deficiency leads to impaired nucleotide, lipid, and energy metabolism. INTERPRETATION: The ENTPD1 locus trait consists of childhood disease-onset, ID, progressive spastic paraparesis, dysarthria, dysmorphisms, and white matter abnormalities with some individuals showing neurocognitive regression. Investigation of an allelic series of ENTPD1: i) expands previously described features of ENTPD1-related neurological disease, ii) highlights the importance of genotype-driven deep phenotyping, iii) documents the need for global collaborative efforts to characterize rare AR disease traits, and iv) provides insights into the disease trait neurobiology. This article is protected by copyright. All rights reserved