Tetratricopeptide repeat domain 7A is a nuclear factor that modulates transcription and chromatin structure

A loss-of-function mutation in tetratricopeptide repeat domain 7A (TTC7A) is a recently identified cause of human intestinal and immune disorders. However, clues to related underlying molecular dysfunctions remain elusive. It is now shown based on the study of TTC7A-deficient and wild-type cells that TTC7A is an essential nuclear protein. It binds to chromatin, preferentially at actively transcribed regions. Its depletion results in broad range of epigenomic changes at proximal and distal transcriptional regulatory elements and in altered control of the transcriptional program. Loss of WT_TTC7A induces general decrease in chromatin compaction, unbalanced cellular distribution of histones, higher nucleosome accessibility to nuclease digestion along with genome instability, and reduced cell viability. Our observations characterize for the first time unreported functions for TTC7A in the nucleus that exert a critical role in chromatin organization and gene regulation to safeguard healthy immune and intestinal status.</p

Integrin Alpha 8 Recessive Mutations Are Responsible for Bilateral Renal Agenesis in Humans

Renal hypodysplasia (RHD) is a heterogeneous condition encompassing a spectrum of kidney development defects including renal agenesis, hypoplasia, and (cystic) dysplasia. Heterozygous mutations of several genes have been identified as genetic causes of RHD with various severity. However, these genes and mutations are not associated with bilateral renal agenesis, except for RET mutations, which could be involved in a few cases. The pathophysiological mechanisms leading to total absence of kidney development thus remain largely elusive. By using a whole-exome sequencing approach in families with several fetuses with bilateral renal agenesis, we identified recessive mutations in the integrin α8-encoding gene ITGA8 in two families. Itga8 homozygous knockout in mice is known to result in absence of kidney development. We provide evidence of a damaging effect of the human ITGA8 mutations. These results demonstrate that mutations of ITGA8 are a genetic cause of bilateral renal agenesis and that, at least in some cases, bilateral renal agenesis is an autosomal-recessive disease

Robust physical methods that enrich genomic regions identical by descent for linkage studies: confirmation of a locus for osteogenesis imperfecta

<p>Abstract</p> <p>Background</p> <p>The monogenic disease osteogenesis imperfecta (OI) is due to single mutations in either of the collagen genes ColA1 or ColA2, but within the same family a given mutation is accompanied by a wide range of disease severity. Although this phenotypic variability implies the existence of modifier gene variants, genome wide scanning of DNA from OI patients has not been reported. Promising genome wide marker-independent physical methods for identifying disease-related loci have lacked robustness for widespread applicability. Therefore we sought to improve these methods and demonstrate their performance to identify known and novel loci relevant to OI.</p> <p>Results</p> <p>We have improved methods for enriching regions of identity-by-descent (IBD) shared between related, afflicted individuals. The extent of enrichment exceeds 10- to 50-fold for some loci. The efficiency of the new process is shown by confirmation of the identification of the Col1A2 locus in osteogenesis imperfecta patients from Amish families. Moreover the analysis revealed additional candidate linkage loci that may harbour modifier genes for OI; a locus on chromosome 1q includes COX-2, a gene implicated in osteogenesis.</p> <p>Conclusion</p> <p>Technology for physical enrichment of IBD loci is now robust and applicable for finding genes for monogenic diseases and genes for complex diseases. The data support the further investigation of genetic loci other than collagen gene loci to identify genes affecting the clinical expression of osteogenesis imperfecta. The discrimination of IBD mapping will be enhanced when the IBD enrichment procedure is coupled with deep resequencing.</p

Converging evidence for an association of ATP2B2 allelic variants with autism in male subjects

Background: Autism is a severe developmental disorder, with strong genetic underpinnings. Previous genome-wide scans unveiled a linkage region spanning 3.5 Mb, located on human chromosome 3p25. This region encompasses the ATP2B2 gene, encoding the plasma membrane calcium-transporting ATPase 2 (PMCA2), which extrudes calcium (Ca2) from the cytosol into the extracellular space. Multiple lines of evidence support excessive intracellular Ca2 signaling in autism spectrum disorder (ASD), making ATP2B2 an attractive candidate gene. Methods: We performed a family-based association study in an exploratory sample of 277 autism genetic resource exchange families and in a replication sample including 406 families primarily recruited in Italy. Results: Several markers were significantly associated with ASD in the exploratory sample, and the same risk alleles at single nucleotide polymorphisms rs3774180, rs2278556, and rs241509 were found associated with ASD in the replication sample after correction for multiple testing. In both samples, the association was present in male subjects only. Markers associated with autism are all comprised within a single block of strong linkage disequilibrium spanning several exons, and the “risk” allele seems to follow a recessive mode of transmission. Conclusions: These results provide converging evidence for an association between ATP2B2 gene variants and autism in male subjects, spurring interest into the identification of functional variants, most likely involved in the homeostasis of Ca2 signaling. Additional support comes from a recent genome-wide association study by the Autism Genome Project, which highlights the same linkage disequilibrium region of the gene

Antitumor activity of an inhibitor of miR-34a in liver cancer with β-catenin-mutations miR-34a oncogenicity in β-catenin-mutated liver cancer

International audienceObjective: Hepatocellular carcinoma (HCC) is the most prevalent primary tumor of the liver. About a third of these tumors presents activating mutations of the β-catenin gene. The molecular pathogenesis of HCC has been elucidated, but mortality remains high and new therapeutic approaches, including treatments based on microRNAs, are required. We aimed to identify candidate microRNAs, regulated by β-catenin, potentially involved in liver tumorigenesis. Design: We used a mouse model, in which β-catenin signaling was overactivated exclusively in the liver, by the tamoxifen-inducible and Cre-Lox-mediated inactivation of the Apc gene. This model develops tumors with properties similar to human HCC. Results: We found that miR-34a was regulated by β-catenin, and significantly induced by the overactivation of β-catenin signaling in mouse tumors and in HCC patients. An inhibitor of miR-34a (LNA-34a) exerted anti-proliferative activity in primary cultures of hepatocyte. This inhibition of proliferation was associated with a decrease in cyclin D1 levels, orchestrated principally by HNF-4α, a target of miR-34a considered to act as a tumor suppressor in the liver. In vivo, LNA-34a approximately halved progression rates for tumors displaying β-catenin activation together with an activation of caspases 2 and 3. Conclusion: This work demonstrates the key oncogenic role of miR-34a in liver tumors with β-catenin gene mutations. We suggest that patients diagnosed with HCC with β-catenin mutations could be treated with an inhibitor of miR-34a. The potential value of this strategy lies in the modulation of the tumor suppressor HNF-4α, which targets cyclin D1, and the induction of a pro-apoptotic program

Tetratricopeptide repeat domain 7A is a nuclear factor that modulates transcription and chromatin structure

Abstract A loss-of-function mutation in tetratricopeptide repeat domain 7A (TTC7A) is a recently identified cause of human intestinal and immune disorders. However, clues to related underlying molecular dysfunctions remain elusive. It is now shown based on the study of TTC7A-deficient and wild-type cells that TTC7A is an essential nuclear protein. It binds to chromatin, preferentially at actively transcribed regions. Its depletion results in broad range of epigenomic changes at proximal and distal transcriptional regulatory elements and in altered control of the transcriptional program. Loss of WT_TTC7A induces general decrease in chromatin compaction, unbalanced cellular distribution of histones, higher nucleosome accessibility to nuclease digestion along with genome instability, and reduced cell viability. Our observations characterize for the first time unreported functions for TTC7A in the nucleus that exert a critical role in chromatin organization and gene regulation to safeguard healthy immune and intestinal status

Association of autism with polymorphisms in the paired-like homeodomain transcription factor 1 () on chromosome 5q31: a candidate gene analysis-2

<p><b>Copyright information:</b></p><p>Taken from "Association of autism with polymorphisms in the paired-like homeodomain transcription factor 1 () on chromosome 5q31: a candidate gene analysis"</p><p>http://www.biomedcentral.com/1471-2350/8/74</p><p>BMC Medical Genetics 2007;8():74-74.</p><p>Published online 6 Dec 2007</p><p>PMCID:PMC2222245.</p><p></p> * 10, position (built 34) = chr5:134.467.793 – 134.639.841). Orientation of gene transcription is indicated by arrows. The bottom panel shows the exon-intron structure of the gene. Two transcripts have been described for the gene, which make use of the same start and stop codons but differ in their respective 5' and 3' UTR regions

Association of autism with polymorphisms in the paired-like homeodomain transcription factor 1 () on chromosome 5q31: a candidate gene analysis-1

<p><b>Copyright information:</b></p><p>Taken from "Association of autism with polymorphisms in the paired-like homeodomain transcription factor 1 () on chromosome 5q31: a candidate gene analysis"</p><p>http://www.biomedcentral.com/1471-2350/8/74</p><p>BMC Medical Genetics 2007;8():74-74.</p><p>Published online 6 Dec 2007</p><p>PMCID:PMC2222245.</p><p></p>type blocks were determined by identifying the first and last markers in a block, which are in strong LD with all intermediate markers. The structure and position of the gene, the positions of the 5 SNPs from the first step genotyping and the 9 SNPS from the second step genotyping are indicated (SNP markers in bold), respectively. LD, linkage disequilibrium; SNP, small nucleotide polymorphism; UTR, 5'-untranslated regions

Mutations in GREB1L Cause Bilateral Kidney Agenesis in Humans and Mice

International audienceCongenital anomalies of the kidney and urinary tract (CAKUT) constitute a major cause of chronic kidney disease in children and 20% of prenatally detected anomalies. CAKUT encompass a spectrum of developmental kidney defects, including renal agenesis, hypoplasia, and cystic and non-cystic dysplasia. More than 50 genes have been reported as mutated in CAKUT-affected case subjects. However, the pathophysiological mechanisms leading to bilateral kidney agenesis (BKA) remain largely elusive. Whole-exome or targeted exome sequencing of 183 unrelated familial and/or severe CAKUT-affected case subjects, including 54 fetuses with BKA, led to the identification of 16 heterozygous variants in GREB1L (growth regulation by estrogen in breast cancer 1-like), a gene reported as a target of retinoic acid signaling. Four loss-of-function and 12 damaging missense variants, 14 being absent from GnomAD, were identified. Twelve of them were present in familial or simplex BKA-affected case subjects. Female BKA-affected fetuses also displayed uterus agenesis. We demonstrated a significant association between GREB1L variants and BKA. By in situ hybridization, we showed expression of Greb1l in the nephrogenic zone in developing mouse kidney. We generated a Greb1l knock-out mouse model by CRISPR-Cas9. Analysis at E13.5 revealed lack of kidneys and genital tract anomalies in male and female Greb1l-/- embryos and a slight decrease in ureteric bud branching in Greb1l+/- embryos. We showed that Greb1l invalidation in mIMCD3 cells affected tubulomorphogenesis in 3D-collagen culture, a phenotype rescued by expression of the wild-type human protein. This demonstrates that GREB1L plays a major role in early metanephros and genital development in mice and humans