Abstract
With homozygosity mapping we have identified two large homozygous regions on chromosome 3q13.11–q13.31 and chromosome 19p13.3–q31.32 in a large Pakistani family suffering from autosomal recessive nonsyndromic hearing impairment (arNSHI). The region on chromosome 19 overlaps with the previously described deafness loci DFNB15, DFNB72 and DFNB95. Mutations in GIPC3 have been shown to underlie the nonsyndromic hearing impairment linked to these loci. Sequence analysis of all exons and exon–intron boundaries of GIPC3 revealed a homozygous canonical splice site mutation, c.226-1G>T, in GIPC3. This is the first mutation described in GIPC3 that affects splicing. The c.226-1G>T mutation is located in the acceptor splice site of intron 1 and is predicted to affect the normal splicing of exon 2. With a minigene assay it was shown to result in the use of an alternative acceptor site in exon 2, resulting in a frameshift and a premature stop codon. This study expands the mutational spectrum of GIPC3 in arNSHI.
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Acknowledgements
We are thankful to the Higher Education Commission, Pakistan for providing Post Doc scholarship to SS to conduct this study in the group of Prof. H. Kremer in the Netherlands. This work was financially supported by a grant from ZorgOnderzoek Nederland / Medische Wetenschappen (40-00812-98-09047, to H.K.).
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Author contributions: SS and JO performed the experiments, SM and MI provided the family for the study. SS did the data analysis. HK provided all reagents/software. SS wrote the paper. RQ, AM, HK and MS supervised the work and critically read the manuscript.
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Siddiqi, S., Ismail, M., Oostrik, J. et al. A canonical splice site mutation in GIPC3 causes sensorineural hearing loss in a large Pakistani family. J Hum Genet 59, 683–686 (2014). https://doi.org/10.1038/jhg.2014.86
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DOI: https://doi.org/10.1038/jhg.2014.86
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