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.
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Acknowledgments
We thank the families for their participation and cooperation. We thank Dr. Jozef Jenca for his kind assistance and Dr. Vasil Janko for discussing the ECG and Echo finding. We also thank Drs. R. Elodie, and R. Yousaf for critique of the manuscript. This work was also supported by the Higher Education Commission and Ministry of Science and Technology, Islamabad, Pakistan, to Sh.R.; the International Center for Genetic Engineering and Biotechnology, Trieste, Italy under project CRP/PAK08-01 Contract No. 08/009 to Sh.R.; National Institute on Deafness and Other Communication Disorders (NIDCD/NIH) research grants R01 DC012564 to Z.M.A.; R01 DC011803 and R01 DC011748 to S.R.; intramural funds from NIDCD DC000039-17 to T.B.F.; Slovak Research and Development Agency under the Contract No. APVV 0148-10 to the Slovak study group and by project implementation (ITMS 26240220051) supported by OPRaD funded by ERDF to D.G.
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Nayak, G., Varga, L., Trincot, C. et al. Molecular genetics of MARVELD2 and clinical phenotype in Pakistani and Slovak families segregating DFNB49 hearing loss. Hum Genet 134, 423–437 (2015). https://doi.org/10.1007/s00439-015-1532-y
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DOI: https://doi.org/10.1007/s00439-015-1532-y