鉴定一种新型II型Usher综合征基因座的候选区域。

Identification of candidate regions for a novel Usher syndrome type II locus.

作者信息

Ben Rebeh Imen, Benzina Zeineb, Dhouib Houria, Hadjamor Imen, Amyere Mustapha, Ayadi Leila, Turki Khalil, Hammami Bouthaina, Kmiha Noureddine, Kammoun Hassen, Hakim Bochra, Charfedine Ilhem, Vikkula Miikka, Ghorbel Abdelmonem, Ayadi Hammadi, Masmoudi Saber

机构信息

Unité Cibles pour le Diagnostic et la Thérapie, Centre de Biotechnologie de Sfax, Tunisie

出版信息

Mol Vis. 2008 Sep 19;14:1719-26.

PMID:18806881

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2538493/

Abstract

PURPOSE

Chronic diseases affecting the inner ear and the retina cause severe impairments to our communication systems. In more than half of the cases, Usher syndrome (USH) is the origin of these double defects. Patients with USH type II (USH2) have retinitis pigmentosa (RP) that develops during puberty, moderate to severe hearing impairment with downsloping pure-tone audiogram, and normal vestibular function. Four loci and three genes are known for USH2. In this study, we proposed to localize the gene responsible for USH2 in a consanguineous family of Tunisian origin.

METHODS

Affected members underwent detailed ocular and audiologic characterization. One Tunisian family with USH2 and 45 healthy controls unrelated to the family were recruited. Two affected and six unaffected family members attended our study. DNA samples of eight family members were genotyped with polymorphic markers. Two-point and multipoint LOD scores were calculated using Genehunter software v2.1. Sequencing was used to investigate candidate genes.

RESULTS

Haplotype analysis showed no significant linkage to any known USH gene or locus. A genome-wide screen, using microsatellite markers, was performed, allowing the identification of three homozygous regions in chromosomes 2, 4, and 15. We further confirmed and refined these three regions using microsatellite and single-nucleotide polymorphisms. With recessive mode of inheritance, the highest multipoint LOD score of 1.765 was identified for the candidate regions on chromosomes 4 and 15. The chromosome 15 locus is large (55 Mb), underscoring the limited number of meioses in the consanguineous pedigree. Moreover, the linked, homozygous chromosome 15q alleles, unlike those of the chromosome 2 and 4 loci, are infrequent in the local population. Thus, the data strongly suggest that the novel locus for USH2 is likely to reside on 15q.

CONCLUSIONS

Our data provide a basis for the localization and the identification of a novel gene implicated in USH2, most likely localized on 15q.

摘要

目的

影响内耳和视网膜的慢性疾病会严重损害我们的沟通系统。在超过半数的病例中，Usher综合征（USH）是这些双重缺陷的根源。II型Usher综合征（USH2）患者患有在青春期发病的色素性视网膜炎（RP）、纯音听力图呈下坡型的中度至重度听力障碍以及正常的前庭功能。已知USH2有四个基因座和三个基因。在本研究中，我们提议在一个突尼斯血统的近亲家庭中定位导致USH2的基因。

方法

对受影响成员进行详细的眼科和听力学特征分析。招募了一个患有USH2的突尼斯家庭以及45名与该家庭无关的健康对照。两名受影响和六名未受影响的家庭成员参与了我们的研究。使用多态性标记对八名家庭成员的DNA样本进行基因分型。使用Genehunter软件v2.1计算两点和多点连锁分析。测序用于研究候选基因。

结果

单倍型分析显示与任何已知的USH基因或基因座均无显著连锁。使用微卫星标记进行了全基因组筛查，在2号、4号和15号染色体上鉴定出三个纯合区域。我们使用微卫星和单核苷酸多态性进一步确认并细化了这三个区域。在隐性遗传模式下，4号和15号染色体上的候选区域的最高多点连锁分析值为1.765。15号染色体基因座很大（55 Mb），这突出了近亲家系中减数分裂数量有限的问题。此外，与2号和4号染色体基因座的等位基因不同，15号染色体q臂上连锁的纯合等位基因在当地人群中很少见。因此，数据强烈表明USH2的新基因座可能位于15q上。