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Loss of ADAMTS19 causes progressive non-syndromic heart valve disease.

ABSTRACT: Valvular heart disease is observed in approximately 2% of the general population¹. Although the initial observation is often localized (for example, to the aortic or mitral valve), disease manifestations are regularly observed in the other valves and patients frequently require surgery. Despite the high frequency of heart valve disease, only a handful of genes have so far been identified as the monogenic causes of disease^2-7. Here we identify two consanguineous families, each with two affected family members presenting with progressive heart valve disease early in life. Whole-exome sequencing revealed homozygous, truncating nonsense alleles in ADAMTS19 in all four affected individuals. Homozygous knockout mice for Adamts19 show aortic valve dysfunction, recapitulating aspects of the human phenotype. Expression analysis using a lacZ reporter and single-cell RNA sequencing highlight Adamts19 as a novel marker for valvular interstitial cells; inference of gene regulatory networks in valvular interstitial cells positions Adamts19 in a highly discriminatory network driven by the transcription factor lymphoid enhancer-binding factor 1 downstream of the Wnt signaling pathway. Upregulation of endocardial Krüppel-like factor 2 in Adamts19 knockout mice precedes hemodynamic perturbation, showing that a tight balance in the Wnt-Adamts19-Klf2 axis is required for proper valve maturation and maintenance.

SUBMITTER: Wunnemann F

PROVIDER: S-EPMC7197892 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Loss of ADAMTS19 causes progressive non-syndromic heart valve disease

Project description:Single-cell transcriptome sequencing of E14.5 mouse hearts from Adamts19 wild-type and Adamts19 knockout animals using Drop-seq.

2019-09-09 | GSE109247 | GEO

Loss of ADAMTS19 causes progressive non-syndromic heart valve disease

Project description:Loss of ADAMTS19 causes progressive non-syndromic heart valve disease

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A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans.

Project description:Deafness, the most frequent sensory deficit in humans, is extremely heterogeneous with hundreds of genes involved. Clinical and genetic analyses of an extended consanguineous family with pre-lingual, moderate-to-profound autosomal recessive sensorineural hearing loss, allowed us to identify CLRN2, encoding a tetraspan protein, as a new deafness gene. Homozygosity mapping followed by exome sequencing identified a 14.96 Mb locus on chromosome 4p15.32p15.1 containing a likely pathogenic missense variant in CLRN2 (c.494C > A, NM_001079827.2) segregating with the disease. Using in vitro RNA splicing analysis, we show that the CLRN2 c.494C > A variant leads to two events: (1) the substitution of a highly conserved threonine (uncharged amino acid) to lysine (charged amino acid) at position 165, p.(Thr165Lys), and (2) aberrant splicing, with the retention of intron 2 resulting in a stop codon after 26 additional amino acids, p.(Gly146Lysfs*26). Expression studies and phenotyping of newly produced zebrafish and mouse models deficient for clarin 2 further confirm that clarin 2, expressed in the inner ear hair cells, is essential for normal organization and maintenance of the auditory hair bundles, and for hearing function. Together, our findings identify CLRN2 as a new deafness gene, which will impact future diagnosis and treatment for deaf patients.

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Mutation of COL11A2 causes autosomal recessive non-syndromic hearing loss at the DFNB53 locus.

Project description:BackgroundAllele variants of COL11A2, encoding collagen type XI alpha2, cause autosomal dominant non-syndromic hearing loss (ARNSHL) at the DFNA13 locus (MIM 601868) and various syndromes that include a deafness phenotype.ObjectiveTo describe a genome-wide scan carried out on a consanguineous Iranian family segregating ARNSHL.ResultsGenotyping data identified a novel locus for ARNSHL on chromosome 6p21.3, which was designated DFNB53. Homozygosity for the P621T mutation of COL11A2 was present in all deaf persons in this family; this same variation was absent in 269 Iranian controls. Sequence comparison of collagen type XI alpha1 and alpha2 peptides across species shows that the replaced proline is an evolutionarily conserved amino acid.ConclusionsThe P621T mutation of COL11A2 affects the Y position of the canonical -Gly-X-Y- repeat in collagens. It lies near the amino-terminus of the triple helical region and causes ARNSHL. This finding suggests that mutation type and location are critical determinants in defining the phenotype of COL11A2 associated diseases.

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Genes in non-syndromic congenital heart disease-CIDR

Project description:Genes in non-syndromic congenital heart disease-CIDR

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Genes in non-syndromic congenital heart disease-CIDR

Project description:Genes in non-syndromic congenital heart disease-CIDR

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Identification of Main Genetic Causes Responsible for Non-Syndromic Hearing Loss in a Peruvian Population.

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| S-EPMC6723399 | biostudies-literature

c.G2114A MYH9 mutation (DFNA17) causes non-syndromic autosomal dominant hearing loss in a Brazilian family.

Project description:We studied a family presenting 10 individuals affected by autosomal dominant deafness in all frequencies and three individuals affected by high frequency hearing loss. Genomic scanning using the 50k Affymetrix microarray technology yielded a Lod Score of 2.1 in chromosome 14 and a Lod Score of 1.9 in chromosome 22. Mapping refinement using microsatellites placed the chromosome 14 candidate region between markers D14S288 and D14S276 (8.85 cM) and the chromosome 22 near marker D22S283. Exome sequencing identified two candidate variants to explain hearing loss in chromosome 14 [PTGDR - c.G894A:p.R298R and PTGER2 - c.T247G:p.C83G], and one in chromosome 22 [MYH9, c.G2114A:p.R705H]. Pedigree segregation analysis allowed exclusion of the PTGDR and PTGER2 variants as the cause of deafness. However, the MYH9 variant segregated with the phenotype in all affected members, except the three individuals with different phenotype. This gene has been previously described as mutated in autosomal dominant hereditary hearing loss and corresponds to DFNA17. The mutation identified in our study is the same described in the prior report. Thus, although linkage studies suggested a candidate gene in chromosome 14, we concluded that the mutation in chromosome 22 better explains the hearing loss phenotype in the Brazilian family.

| S-EPMC4261959 | biostudies-literature

Raptor/mTORC1 loss in adipocytes causes progressive lipodystrophy and fatty liver disease.

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| S-EPMC4877665 | biostudies-literature

Loss of Axin2 results in impaired heart valve maturation and subsequent myxomatous valve disease.

Project description:AimsMyxomatous valve disease (MVD) is the most common aetiology of primary mitral regurgitation. Recent studies suggest that defects in heart valve development can lead to heart valve disease in adults. Wnt/?-catenin signalling is active during heart valve development and has been reported in human MVD. The consequences of increased Wnt/?-catenin signalling due to Axin2 deficiency in postnatal valve remodelling and pathogenesis of MVD were determined.Methods and resultsTo investigate the role of Wnt/?-catenin signalling, we analysed heart valves from mice deficient in Axin2 (KO), a negative regulator of Wnt/?-catenin signalling. Axin2 KO mice display enlarged mitral and aortic valves (AoV) after birth with increased Wnt/?-catenin signalling and cell proliferation, whereas Sox9 expression and collagen deposition are decreased. At 2 months in Axin2 KO mice, the valve extracellular matrix (ECM) is stratified but distal AoV leaflets remain thickened and develop aortic insufficiency. Progressive myxomatous degeneration is apparent at 4 months with extensive ECM remodelling and focal aggrecan-rich areas, along with increased BMP signalling. Infiltration of inflammatory cells is also observed in Axin2 KO AoV prior to ECM remodelling. Overall, these features are consistent with the progression of human MVD. Finally, Axin2 expression is decreased and Wnt/?-catenin signalling is increased in myxomatous mitral valves in a murine model of Marfan syndrome, supporting the importance of Wnt/?-catenin signalling in the development of MVD.ConclusionsAltogether, these data indicate that Axin2 limits Wnt/?-catenin signalling after birth and allows proper heart valve maturation. Moreover, dysregulation of Wnt/?-catenin signalling resulting from loss of Axin2 leads to progressive MVD.

| S-EPMC5220675 | biostudies-literature

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