TY - JOUR
T1 - Molecular genetics of MARVELD2 and clinical phenotype in Pakistani and Slovak families segregating DFNB49 hearing loss
AU - Nayak, Gowri
AU - Varga, Lukas
AU - Trincot, Claire
AU - Shahzad, Mohsin
AU - Friedman, Penelope L.
AU - Klimes, Iwar
AU - Greinwald, John H.
AU - Riazuddin, S. Amer
AU - Masindova, Ivica
AU - Profant, Milan
AU - Khan, Shaheen N.
AU - Friedman, Thomas B.
AU - Ahmed, Zubair M.
AU - Gasperikova, Daniela
AU - Riazuddin, Sheikh
AU - Riazuddin, Saima
N1 - Publisher Copyright:
© 2015, Springer-Verlag Berlin Heidelberg.
PY - 2015/3/10
Y1 - 2015/3/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84925490344&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84925490344&partnerID=8YFLogxK
U2 - 10.1007/s00439-015-1532-y
DO - 10.1007/s00439-015-1532-y
M3 - Article
C2 - 25666562
AN - SCOPUS:84925490344
SN - 0340-6717
VL - 134
SP - 423
EP - 437
JO - Human genetics
JF - Human genetics
IS - 4
ER -