Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Am J Hum Genet. 2010 Nov 12;87(5):708-12. doi: 10.1016/j.ajhg.2010.10.009. Epub 2010 Oct 28.
Fibrochondrogenesis is a severe, autosomal-recessive, short-limbed skeletal dysplasia. In a single case of fibrochondrogenesis, whole-genome SNP genotyping identified unknown ancestral consanguinity by detecting three autozygous regions. Because of the predominantly skeletal nature of the phenotype, the 389 genes localized to the autozygous intervals were prioritized for mutation analysis by correlation of their expression with known cartilage-selective genes via the UCLA Gene Expression Tool, UGET. The gene encoding the α1 chain of type XI collagen (COL11A1) was the only cartilage-selective gene among the three candidate intervals. Sequence analysis of COL11A1 in two genetically independent fibrochondrogenesis cases demonstrated that each was a compound heterozygote for a loss-of-function mutation on one allele and a mutation predicting substitution for a conserved triple-helical glycine residue on the other. The parents who were carriers of missense mutations had myopia. Early-onset hearing loss was noted in both parents who carried a loss-of-function allele, suggesting COL11A1 as a locus for mild, dominantly inherited hearing loss. These findings identify COL11A1 as a locus for fibrochondrogenesis and indicate that there might be phenotypic manifestations among carriers.
纤维软骨生成症是一种严重的常染色体隐性短肢骨骼发育不良症。在一例纤维软骨生成症中，通过检测三个纯合区域，全基因组 SNP 基因分型确定了未知的祖先近亲婚配。由于表型主要是骨骼性质，通过 UCLA 基因表达工具 UGET 将其表达与已知的软骨选择性基因进行相关性分析，将定位在纯合间隔内的 389 个基因优先进行突变分析。编码 XI 型胶原α1 链的基因（COL11A1）是三个候选间隔中唯一的软骨选择性基因。在两个独立的纤维软骨生成症病例中对 COL11A1 进行的序列分析表明，每个病例都是一个等位基因上的功能丧失突变的复合杂合子，另一个等位基因上预测为保守三螺旋甘氨酸残基的取代突变。携带错义突变的父母都患有近视。携带功能丧失等位基因的父母均出现早发性听力损失，提示 COL11A1 是轻度显性遗传性听力损失的一个位点。这些发现确定了 COL11A1 是纤维软骨生成症的一个位点，并表明携带者可能存在表型表现。
