Mutations in the Gene Encoding the RER Protein FKBP65 Cause Autosomal-Recessive Osteogenesis Imperfecta
Mutations in the Gene Encoding the RER Protein FKBP65 Cause Autosomal-Recessive Osteogenesis Imperfecta
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DOI：
10.1016/j.ajhg.2010.02.022
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发表时间：
2010-04-09
影响因子：
9.8
通讯作者：
Krakow, Deborah
中科院分区：
文献类型：
--
作者：
Alanay, Yasemin;Avaygan, Hrispima;Krakow, Deborah
成骨不全是一种临床和遗传异质性的脆性骨疾病，由I型前胶原的合成、结构或翻译后修饰缺陷引起。OI的显性形式由编码I型前胶原异源三聚体链的COL 1A 1或COL 1A 2突变引起。最轻微形式的OI通常是由于结构正常的1型前胶原合成减少所致，而中度至致死形式的OI通常是由于1型前胶原链之一的结构缺陷所致。Recombinant遗传的OI，通常表型上是严重的，最近已被证明是由脯氨酰-3-羟化酶复合物的缺陷导致的，该缺陷导致α 1（I）三螺旋结构域的残基986处缺少单个3-羟脯氨酸。我们研究了一个队列的5个血缘关系的土耳其家庭，来自土耳其的黑海地区，中度严重的recording遗传OI和确定了一个新的基因座OI的17号染色体上。在这些家庭，并在墨西哥裔美国人的家庭，纯合性突变FKBP 10，它编码FKBP 65，分子伴侣，参与1型前胶原折叠，被确定。此外，我们确定FKBP 10突变影响I型前胶原分泌。这些发现确定了一个以前未被认识的机制，在发病机制的OI。
Osteogenesis imperfecta is a clinically and genetically heterogeneous brittle bone disorder that results from defects in the synthesis, structure, or posttranslational modification of type I procollagen. Dominant forms of OI result from mutations in COL1A1 or COL1A2, which encode the chains of the type I procollagen heterotrimer. The mildest form of OI typically results from diminished synthesis of structurally normal type 1 procollagen, whereas moderately severe to lethal forms of OI usually result from structural defects in one of the type 1 procollagen chains. Recessively inherited OI, usually phenotypically severe, has recently been shown to result from defects in the prolyl-3-hydroxylase complex that lead to the absence of a single 3-hydroxyproline at residue 986 of the alpha 1 (I) triple helical domain. We studied a cohort of five consanguineous Turkish families, originating from the Black Sea region of Turkey, with moderately severe recessively inherited OI and identified a novel locus for OI on chromosome 17. In these families, and in a Mexican-American family, homozygosity for mutations in FKBP10, which encodes FKBP65, a chaperone that participates in type 1 procollagen folding, was identified. Further, we determined that FKBP10 mutations affect type I procollagen secretion. These findings identify a previously unrecognized mechanism in the pathogenesis of OI.