| Affiliation: | 1.Division of Pediatric Otolaryngology,Cincinnati Children’s Hospital Medical Center,Cincinnati,USA;2.Department of Otorhinolaryngology, Head and Neck Surgery, Faculty of Medicine and University Hospital,Comenius University,Bratislava,Slovakia;3.Diabgene, Institute of Experimental Endocrinology, Slovak Academy of Sciences,Bratislava,Slovakia;4.Department of Otorhinolaryngology Head and Neck Surgery,School of Medicine, University of Maryland,Baltimore,USA;5.Internal Medicine Consult Service, Hatfield Clinical Research Center,National Institutes of Health,Bethesda,USA;6.National Center of Excellence in Molecular Biology,University of the Punjab,Lahore,Pakistan;7.The Wilmer Eye Institute,Johns Hopkins University School of Medicine,Baltimore,USA;8.Laboratory of Molecular Genetics,National Institute On Deafness and Other Communication Disorders, Porter Neuroscience Research Center, National Institutes of Health,Bethesda,USA;9.Centre for Molecular Medicine, Slovak Academy of Sciences,Bratislava,Slovakia;10.Allama Iqbal Medical College-Jinnah Hospital Complex,University of Health Sciences,Lahore,Pakistan;11.University of Lahore,Lahore,Pakistan;12.Shaheed Zulfiqar Ali Bhutto Medical University,Islamabad,Pakistan |
| 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. |
