Filamin B (FLNB) functions as a switch that can affect chrondrocyte development and endochondral bone formation through a series of signaling molecules and transcription factors that also affect ...Sertoli cell development. Here, we report a subject with a novel skeletal dysplasia and co‐existing 46,XY gonadal dysgenesis and biallelic mutations in FLNB. Whole exome sequencing was performed to identify mutations. Quantitative polymerase chain reaction (qPCR) and flow variant assays were performed to quantify RNA, proteins and phosphorylated proteins. The TOPFLASH reporter was performed to quantify β‐catenin activity. Mutations were identified in the FLNB gene (FLNB:p.F964L, FLNB:p.A1577V). These mutations increased binding of FLNB protein to the MAP3K1 and RAC1 signal transduction complex and activated β‐catenin and had different effects on phosphorylation of MAP kinase pathway intermediates and SOX9 expression. Direct activation of β‐catenin through the FLNB‐MAP3K1‐RAC1 complex by FLNB mutations is a novel mechanism for causing 46,XY gonadal dysgenesis. The mechanism of action varies from those reported previously for loss of function mutations in SOX9 and gain‐of‐function mutations in MAP3K1.
Molecular pathogenesis of 46,XY DSD with skeletal dysplasia.
Loke J, Ostrer H. Rapidly screening variants of uncertain significance in the MAP3K1 gene for phenotypic effects.
DNA sequencing of candidate genes or whole exomes on a diagnostic or investigational ...basis will yield a plethora of variants of uncertain significance whose potential phenotypic roles cannot be readily demonstrated by prediction programs, SNP databases nor conventional genetic analysis. Many variants may produce phenotypic changes in the encoded proteins by affecting the quantity, post‐translational modification or protein interactions. Here, we establish the application of the method of flow cytometry following immunoprecipitation to show that known protein interactions are altered in the B‐lymphoblastoid cells of patients with 46,XY gonadal dysgenesis arising from mutations in the MAP3K1 gene. This method can be scaled readily to test multiple interactions for many variants simultaneously from available tissues as well as quantify the effects of variants on protein accumulation and post‐translational modification, thus providing an efficient means for screening variants of uncertain significance for phenotypic effects.
Haplotypes constructed from Y-chromosome markers were used to trace the paternal origins of the Jewish Diaspora. A set of 18 biallelic polymorphisms was genotyped in 1,371 males from 29 populations, ...including 7 Jewish (Ashkenazi, Roman, North African, Kurdish, Near Eastern, Yemenite, and Ethiopian) and 16 non-Jewish groups from similar geographic locations. The Jewish populations were characterized by a diverse set of 13 haplotypes that were also present in non-Jewish populations from Africa, Asia, and Europe. A series of analyses was performed to address whether modern Jewish Y-chromosome diversity derives mainly from a common Middle Eastern source population or from admixture with neighboring non-Jewish populations during and after the Diaspora. Despite their long-term residence in different countries and isolation from one another, most Jewish populations were not significantly different from one another at the genetic level. Admixture estimates suggested low levels of European Y-chromosome gene flow into Ashkenazi and Roman Jewish communities. A multidimensional scaling plot placed six of the seven Jewish populations in a relatively tight cluster that was interspersed with Middle Eastern non-Jewish populations, including Palestinians and Syrians. Pairwise differentiation tests further indicated that these Jewish and Middle Eastern non-Jewish populations were not statistically different. The results support the hypothesis that the paternal gene pools of Jewish communities from Europe, North Africa, and the Middle East descended from a common Middle Eastern ancestral population, and suggest that most Jewish communities have remained relatively isolated from neighboring non-Jewish communities during and after the Diaspora.
Modern day Latin America resulted from the encounter of Europeans with the indigenous peoples of the Americas in 1492, followed by waves of migration from Europe and Africa. As a result, the genomic ...structure of present day Latin Americans was determined both by the genetic structure of the founding populations and the numbers of migrants from these different populations. Here, we analyzed DNA collected from two well-established communities in Colorado (33 unrelated individuals) and Ecuador (20 unrelated individuals) with a measurable prevalence of the
BRCA1
c.185delAG and the
GHR
c.E180 mutations, respectively, using Affymetrix Genome-wide Human SNP 6.0 arrays to identify their ancestry. These mutations are thought to have been brought to these communities by Sephardic Jewish progenitors. Principal component analysis and clustering methods were employed to determine the genome-wide patterns of continental ancestry within both populations using single nucleotide polymorphisms, complemented by determination of Y-chromosomal and mitochondrial DNA haplotypes. When examining the presumed
European
component of these two communities, we demonstrate enrichment for Sephardic Jewish ancestry not only for these mutations, but also for other segments as well. Although comparison of both groups to a reference Hispanic/Latino population of Mexicans demonstrated proximity and similarity to other modern day communities derived from a European and Native American two-way admixture, identity-by-descent and Y-chromosome mapping demonstrated signatures of Sephardim in both communities. These findings are consistent with historical accounts of Jewish migration from the realms that comprise modern Spain and Portugal during the Age of Discovery. More importantly, they provide a rationale for the occurrence of mutations typically associated with the Jewish Diaspora in Latin American communities.
Mitral valve prolapse (MVP) is a very common clinical condition that refers to a systolic billowing of one or both mitral valve leaflets into the left atrium. Improvements of echocardiographic ...techniques and new insights in mitral valve anatomy and physiology have rendered the diagnosis of this condition more accurate and reliable. MVP can be sporadic or familial, demonstrating autosomal dominant and X‐linked inheritance. Three different loci on chromosomes 16, 11 and 13 have been found to be linked to MVP, but no specific gene has been described. Another locus on chromosome X was found to cosegregate with a rare form of MVP called ‘X‐linked myxomatous valvular dystrophy’. MVP is more frequent in patients with connective tissue disorders including Marfan syndrome, Ehlers–Danlos and osteogenesis imperfecta. The purpose of this review is to describe previous studies on the genetics and prevalence of MVP. The report warrants the need for further genetically based studies on this common, albeit not fully understood, clinical entity.
Objective. One way in which parity and use of oral contraceptives may protect against ovarian cancer is by preventing inflammation and oxidative stress associated with ovulation. Since the genes ...superoxide dismutase (
SOD2), myeloperoxidase (
MPO), and NAD(P)H:quinone oxidoreductase 1 (
NQO1) are involved in inflammation and oxidative stress, we investigated whether variants of these genes are associated with risk of ovarian cancer.
Methods. In a hospital-based case-control study, we compared 125 cases and 193 controls with respect to prevalence of (1) the T→C (val→ala) substitution at the −9 position in the signal sequence of
SOD2; (2) the G→A substitution at the −463 position in the promoter region of
MPO; and (3) the C→T (pro→ser) change in exon 6 of
NQO1. Genotyping was done using PCR and gel electrophoresis for
MPO and
NQO1 and using MALDI-TOF mass spectrometry for
SOD2.
Results. For
SOD2, women with the TC (val/ala) or CC (ala/ala) genotypes were at increased risk odds ratio (OR) 2.1, 95% confidence interval (CI) 1.1–4.0. Results for
MPO and
NQO1 were in the hypothesized directions but were not statistically significant. For
MPO, there was a small inverse association among women with GA or AA genotypes (OR = 0.72, 95% CI 0.43–1.2). For
NQO1, the TT (ser/ser) genotype was associated with somewhat increased risk (OR = 2.3, 95% CI 0.69–7.6).
Conclusions. While these results need to be confirmed in other studies, they point to a possible role for genes involved in oxidative stress in the development of ovarian cancer.
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