Haplogroup analysis supports a pathogenic role for the 7510T>C mutation of mitochondrial tRNA^Ser(UCN) in sensorineural hearing loss

Abstract

We ascertained a large North American family, LMG309, with matrilineal transmission of non-syndromic, progressive sensorineural hearing loss (SNHL). There was no history of aminoglycoside exposure, and penetrance was complete. We sequenced the entire mitochondrial genome and identified the previously reported 7510T>C transition in the tRNA(Ser(UCN)) gene. The 7510T>C was homoplasmic in all affected members. The LMG309 mitochondrial sequence belongs to an unnamed subgroup of mitochondrial haplogroup H. We demonstrate that the previously reported Spanish family S258 carries 7510T>C on a different mitochondrial sub-haplogroup, H1. We did not detect 7510T>C among 79 Caucasian haplogroup H control samples, including 11 from sub-haplogroup H1 and one from the same sub-haplogroup as LMG309. Our results provide strong genetic evidence that 7510T>C is a pathogenic mutation that causes non-syndromic SNHL.

Non-syndromic Hearing Impairment in a Hungarian Family with the m.7510T>C Mutation of Mitochondrial tRNASer(UCN) and Review of Published Cases

“…Our index patient had a delay in fine motor skills and coordination at the age of 4.5 years when his hearing loss became evident, but no other organ involvement (renal, cardiac, opthalmologic, endocrine) could be detected. As accompanying neurological symptoms, episodes of sudden, severe, and self-limiting vertigo; chronic or intermittent spontaneous bilateral tinnitus; and worsening of the symptoms after noise exposure were reported in the third North American family (Labay et al 2008). Penetrance and age of onset of the disease differed within the pedigrees reported so far (Hutchin et al 2000;Castillo et al 2002;Labay et al 2008).…”

“…In all published families, symptoms appeared mainly as isolated hearing loss. There were no reports of cardiac, ophthalmologic, or renal involvement or movement disorder in the affected family members (Hutchin et al 2000;Castillo et al 2002;Labay et al 2008). Our index patient had a delay in fine motor skills and coordination at the age of 4.5 years when his hearing loss became evident, but no other organ involvement (renal, cardiac, opthalmologic, endocrine) could be detected.…”

“…The second extended Spanish family carried the homoplasmic mutation on sub-haplogroup H1 (Castillo et al 2002), while the third reported family, of North American origin, carried the mutation on an unnamed subgroup of mitochondrial haplogroup H (Labay et al 2008). The m.7510T>C mtDNA mutation was not detected in normal Caucasian controls (Hutchin et al 2000), nor in haplogroup-or sub-haplogroupmatched controls (Labay et al 2008). Although it was not found in some large screening populations with nonsyndromic SNHL (Jacobs et al 2005;Lévêque et al 2007), several families have already been described.…”

“…In the originally reported Caucasian family from the United Kingdom, the mutation was present in very high levels of heteroplasmy in blood with no available data on the haplogroup background (Hutchin et al 2000). The second extended Spanish family carried the homoplasmic mutation on sub-haplogroup H1 (Castillo et al 2002), while the third reported family, of North American origin, carried the mutation on an unnamed subgroup of mitochondrial haplogroup H (Labay et al 2008). The m.7510T>C mtDNA mutation was not detected in normal Caucasian controls (Hutchin et al 2000), nor in haplogroup-or sub-haplogroupmatched controls (Labay et al 2008).…”

“…The m.7510T>C alteration in the tRNA Ser(UCN) was previously regarded as a rare variant, originally identified in three large families with matrilineal non-syndromic SNHL (Hutchin et al 2000;Castillo et al 2002;Labay et al 2008). In the originally reported Caucasian family from the United Kingdom, the mutation was present in very high levels of heteroplasmy in blood with no available data on the haplogroup background (Hutchin et al 2000).…”