title: Molecular genetics of MARVELD2 and clinical phenotype in Pakistani and Slovak families segregating DFNB49 hearing loss.
abstract: Pathogenic mutations of MARVELD2, encoding tricellulin, a tricelluar tight junction protein, cause autosomal recessive non-syndromic hearing loss (DFNB49) in families of Pakistan and Czech Roma origin. In fact, they are a significant cause of prelingual hearing loss in the Czech Roma, second only to GJB2 variants. Previously, we reported that mice homozygous for p.Arg497* variant of Marveld2 had a broad phenotypic spectrum, where defects were observed in the inner ear, heart, mandibular salivary gland, thyroid gland and olfactory epithelium. The current study describes the types and frequencies of MARVELD2 alleles and clinically reexamines members of DFNB49 families. We found that MARVELD2 variants are responsible for about 1.5 % (95 % CI 0.8-2.6) of non-syndromic hearing loss in our cohort of 800 Pakistani families. The c.1331+2T>C allele is recurrent. In addition, we identified a novel large deletion in a single family, which appears to have resulted from non-allelic homologous recombination between two similar Alu short interspersed elements. Finally, we observed no other clinical manifestations co-segregating with hearing loss in DFNB49 human families, and hypothesize that the additional abnormalities in the Marveld2 mutant mouse indicates a critical non-redundant function for tricellulin in other organ systems.
authors: Division of Pediatric Otolaryngology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
authors: Gowri
authors: G
authors: Nayak
authors: Lukas
authors: L
authors: Varga
authors: Claire
authors: C
authors: Trincot
authors: Mohsin
authors: M
authors: Shahzad
authors: Penelope L
authors: PL
authors: Friedman
authors: Iwar
authors: I
authors: Klimes
authors: John H
authors: JH
authors: Greinwald
authors: S Amer
authors: SA
authors: Riazuddin
authors: Ivica
authors: I
authors: Masindova
authors: Milan
authors: M
authors: Profant
authors: Shaheen N
authors: SN
authors: Khan
authors: Thomas B
authors: TB
authors: Friedman
authors: Zubair M
authors: ZM
authors: Ahmed
authors: Daniela
authors: D
authors: Gasperikova
authors: Sheikh
authors: S
authors: Riazuddin
authors: Saima
authors: S
authors: Riazuddin
mesh_terms: D000293:Adolescent; D000818:Animals; D002478:Cells, Cultured; D002648:Child; D000072259:Connexin 26; D017630:Connexins; D004252:DNA Mutational Analysis; D004285:Dogs; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D062794:MARVEL Domain Containing 2 Protein / Q000235:genetics*; D008297:Male; D010154:Pakistan; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018154:Slovakia
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D062794:MARVEL Domain Containing 2 Protein; C516798:MARVELD2 protein, human; D000072259:Connexin 26