TY  - JOUR
A1  - Hofrichter, Michaela A. H.
A1  - Mojarad, Majid
A1  - Doll, Julia
A1  - Grimm, Clemens
A1  - Eslahi, Atiye
A1  - Hosseini, Neda Sadat
A1  - Rajati, Mohsen
A1  - Müller, Tobias
A1  - Dittrich, Marcus
A1  - Maroofian, Reza
A1  - Haaf, Thomas
A1  - Vona, Barbara
T1  - The conserved p.Arg108 residue in S1PR2 (DFNB68) is fundamental for proper hearing: evidence from a consanguineous Iranian family
JF  - BMC Medical Genetics
N2  - Background:
Genetic heterogeneity and consanguineous marriages make recessive inherited hearing loss in Iran the second most common genetic disorder. Only two reported pathogenic variants (c.323G>C, p.Arg108Pro and c.419A>G, p.Tyr140Cys) in the S1PR2 gene have previously been linked to autosomal recessive hearing loss (DFNB68) in two Pakistani families. We describe a segregating novel homozygous c.323G>A, p.Arg108Gln pathogenic variant in S1PR2 that was identified in four affected individuals from a consanguineous five generation Iranian family.

Methods:
Whole exome sequencing and bioinformatics analysis of 116 hearing loss-associated genes was performed in an affected individual from a five generation Iranian family. Segregation analysis and 3D protein modeling of the p.Arg108 exchange was performed.

Results:
The two Pakistani families previously identified with S1PR2 pathogenic variants presented profound hearing loss that is also observed in the affected Iranian individuals described in the current study. Interestingly, we confirmed mixed hearing loss in one affected individual. 3D protein modeling suggests that the p.Arg108 position plays a key role in ligand receptor interaction, which is disturbed by the p.Arg108Gln change.

Conclusion:
In summary, we report the third overall mutation in S1PR2 and the first report outside the Pakistani population. Furthermore, we describe a novel variant that causes an amino acid exchange (p.Arg108Gln) in the same amino acid residue as one of the previously reported Pakistani families (p.Arg108Pro). This finding emphasizes the importance of the p.Arg108 amino acid in normal hearing and confirms and consolidates the role of S1PR2 in autosomal recessive hearing loss.
KW  - 3D modeling
KW  - autosomal recessive non-synstromic hearing loss
KW  - DFNB68
KW  - mixed hearing loss
KW  - whole exome sequencing
KW  - S1PR2
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-175755
VL  - 19
IS  - 81
ER  -