Autosomal recessive nonsyndromic deafness locus DFNB63 at chromosome 11q13.2–q13.3

Abstract

A genome wide linkage analysis of nonsyndromic deafness segregating in a consanguineous Pakistani family (PKDF537) was used to identify DFNB63, a new locus for congenital profound sensorineural hearing loss. A maximum two-point lod score of 6.98 at theta = 0 was obtained for marker D11S1337 (68.55 cM). Genotyping of 550 families revealed three additional families (PKDF295, PKDF702 and PKDF817) segregating hearing loss linked to chromosome 11q13.2-q13.3. Meiotic recombination events in these four families define a critical interval of 4.81 cM bounded by markers D11S4113 (68.01 cM) and D11S4162 (72.82 cM), and SHANK2, FGF-3, TPCN2 and CTTN are among the candidate genes in this interval. Positional identification of this deafness gene should reveal a protein necessary for normal development and/or function of the auditory system.

Calcium signaling via two-pore channels: local or global, that is the question

“…This locus has been linked with human chromosome location 11q13.2-13.3 (46), which also contains the gene encoding human TPC2 ( TPCN2 ). However, sequencing of the coding regions for the 13 candidate genes, including TPCN2 , from an affected individual identified no disease-causing mutations (44).…”

The acid test: the discovery of two-pore channels (TPCs) as NAADP-gated endolysosomal Ca2+ release channels

“…This would be consistent with the lysosomal function of TPC2 in melanosomes, lysosomal-related organelles of the melanocytes, which produce and release melanin to keratinocytes for pigmentation. The TPCN 2 locus is also within the chromosomal region that is linked to autosomal recessive nonsyndromic hearing impairment in at least five families (29, 31), and for one of them, the TPCN2 gene has been sequenced to show five exonic and four intronic variants (29). Given that progressive hearing loss has been linked to several lysosomal storage diseases (30), it is possible that dysfunction of the lysosomal Ca 2+ release channel, TPC2, contributes to this disease.…”

Integration of Tmc1/2 into the mechanotransduction complex in zebrafish hair cells is regulated by Transmembrane O-methyltransferase (Tomt)

“…The human ortholog of the tomt gene is called Leucine Rich and O-Methyltransferase Containing ( LRTOMT ), a dual reading frame locus that codes for either Leucine-Rich Repeat Containing 51 (LRTOMT1 / LRRC51) or TOMT (LRTOMT2). Mutations in LRTOMT2 are responsible for DFNB63, a non-syndromic, autosomal recessive form of human deafness that is characterized by severe to profound neurosensory hearing loss that can be congenital or prelingual (Ahmed et al, 2008; Du et al, 2008; Kalay et al, 2007; Khan et al, 2007; Tlili et al, 2007). No vestibular dysfunction has been described for DFNB63 patients.…”