Ballana Ester, Mercader Josep Maria, Fischel-Ghodsian Nathan, Estivill Xavier
Genes and Disease Program, Centre for Genomic Regulation (CRG), Barcelona, Catalonia, Spain.
BMC Med Genet. 2007 Dec 21;8:81. doi: 10.1186/1471-2350-8-81.
Mitochondrial DNA (mtDNA) mutations account for at least 5% of cases of postlingual, nonsyndromic hearing impairment. Among them, mutation A1555G is frequently found associated with aminoglycoside-induced and/or nonsyndromic hearing loss in families presenting with extremely variable clinical phenotypes. Biochemical and genetic data have suggested that nuclear background is the main factor involved in modulating the phenotypic expression of mutation A1555G. However, although a major nuclear modifying locus was located on chromosome 8p23.1 and regardless intensive screening of the region, the gene involved has not been identified.
With the aim to gain insights into the factors that determine the phenotypic expression of A1555G mutation, we have analysed in detail different genetic and genomic elements on 8p23.1 region (DEFA3 gene absence, CLDN23 gene and MRPS18CP2 pseudogene) in a group of 213 A1555G carriers.
Family based association studies identified a positive association for a polymorphism on MRPS18CP2 and an overrepresentation of DEFA3 gene absence in the deaf group of A1555G carriers.
Although none of the factors analysed seem to have a major contribution to the phenotype, our findings provide further evidences of the involvement of 8p23.1 region as a modifying locus for A1555G 12S rRNA gene mutation.
线粒体DNA（mtDNA）突变至少占语后非综合征性听力损失病例的5%。其中，A1555G突变在临床表型极其多样的家族中常与氨基糖苷类药物诱导的和/或非综合征性听力损失相关。生化和遗传数据表明，核背景是调节A1555G突变表型表达的主要因素。然而，尽管一个主要的核修饰位点定位于8号染色体p23.1区域，且对该区域进行了深入筛查，但相关基因尚未确定。
为深入了解决定A1555G突变表型表达的因素，我们对213名A1555G携带者组成的群体中8p23.1区域的不同遗传和基因组元件（DEFA3基因缺失、CLDN23基因和MRPS18CP2假基因）进行了详细分析。
基于家系的关联研究发现，MRPS18CP2上的一个多态性存在正相关，且在A1555G携带者的聋人组中DEFA3基因缺失的比例过高。
尽管所分析的因素似乎均未对表型有主要影响，但我们的研究结果进一步证明了8p23.1区域作为A1555G 12S rRNA基因突变修饰位点的作用。
