Age at onset-dependent presentations of premature hip osteoarthritis, avascular necrosis of the femoral head, or Legg-Calve-Perthes disease in a single family, consequent upon a p.Gly1170Ser mutation of COL2A1
Age at onset-dependent presentations of premature hip osteoarthritis, avascular necrosis of the femoral head, or Legg-Calve-Perthes disease in a single family, consequent upon a p.Gly1170Ser mutation of COL2A1
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COL2A1 的 p.Gly1170Ser 突变导致单个家族出现过早髋骨关节炎、股骨头缺血性坏死或 Legg-Calve-Perthes 病的发病年龄依赖性表现
DOI：
10.1002/art.23491
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发表时间：
2008-06-01
影响因子：
--
通讯作者：
Wang, Yiming
中科院分区：
文献类型：
--
作者：
Su, Peiqiang;Li, Ru;Wang, Yiming
Objective.确定一个家族中导致骨关节炎（OA）、股骨头缺血性坏死（AVN）和股骨头缺血性坏死（Legg-Calve-Perthes病）的遗传异常，并确定不同家族成员表现出不同表型的相关因素。招募了一个5代家庭的42名成员进行调查。诊断由独立的骨科医生和放射科医生进行。观察病变组织的病理学变化。用跨越COL 2A 1基因座的标记进行连锁分析。构建单倍型并检测基因突变。对野生型和突变蛋白的结构进行了建模。结果。确定了16名受影响的成员（5名孤立性早熟髋关节OA，6名股骨头AVN，5名Legg-Calve-Perthes病）。COL 2A 1的p.Gly1170Ser突变与3种疾病共分离，在对照中不存在。值得注意的是，与股骨头骨骺闭合状态相关的发病年龄与疾病相关，Legg-Calve-Perthes病在闭合前出现（6-14岁），股骨头AVN在闭合期间出现（15-18岁），髋关节早熟OA在闭合后出现（21-34岁）。分子模拟预测丝氨酸到甘氨酸的取代使蛋白质的螺旋结构松动。该家族中COL 2A 1的p.Gly1170Ser突变导致局限于髋关节的病理，表现为孤立性早熟髋关节OA、股骨头AVN或Legg-Calve-Perthes病。发病年龄与股骨头骨骺闭合的关系似乎是决定疾病模式的关键因素。
Objective. To identify the genetic abnormality responsible for osteoarthritis (OA), avascular necrosis (AVN) of the femoral head, and Legg-Calve-Perthes disease in a single family, and to determine factors responsible for the distinct phenotypes manifested by different family members.Methods. Forty-two members of a 5-generation family were recruited and investigated. Diagnosis was made by independent orthopedic surgeons and radiologists. Histopathologic changes of the diseased tissue were examined. Linkage analysis was performed with markers spanning the COL2A1 locus. Haplotypes were constructed and mutation of the gene was detected. Structures of the wild-type and mutant proteins were modeled.Results. Sixteen affected members were identified (5 with isolated precocious hip OA, 6 with AVN of the femoral head, and 5 with Legg-Calve-Perthes disease). A p.Gly1170Ser mutation of COL2A1 cosegregated with the 3 diseases and was absent in controls. Of note, age at onset in relation to the closure status of the femoral head epiphysis was associated with the diseases, with Legg-Calve-Perthes disease presenting prior to closure (at ages 6-14 years), AVN of the femoral head presenting during closure (at ages 15-18 years), and precocious OA of the hip presenting after closure (at ages 21-34 years). Molecular modeling predicted that the serine-to-glycine substitution loosens the helical structure of the protein.Conclusion. The p.Gly1170Ser mutation of COL2A1 in the family described is responsible for pathology confined to the hip joint, which presents as isolated precocious hip OA, AVN of the femoral head, or Legg-Calve-Perthes disease. Age at onset in relation to closure of the femoral head epiphysis appears to be a critical factor in determining disease pattern.