罕见黏多糖贮积症ⅣA型致病基因GALNS突变谱和骨骼表型

GALNS mutation spectrum and bone phenotype of mucopolysaccharidosis type ⅣA

目的分析罕见黏多糖贮积症ⅣA型(mucopolysaccharidosis typeⅣA,MPSⅣA)家系患者的临床特点,行致病基因突变研究,探讨MPSⅣA患者骨骼表型与基因突变谱的特点。方法纳入以步态异常、骨骼畸形为主要表现的3个家系4例患者,评估患者临床表现、骨转换生化指标、骨密度、骨影像学及MPS相关酶学指标。采用全外显子测序技术检测致病基因突变。复习文献,总结我国大样本MPSⅣA患者表型及基因型特点。结果MPSⅣA型主要表型包括身材矮小(74.0%)、关节松弛(53.0%)、鸡胸(39.0%)、漏斗胸(36.0%)、膝内翻/外翻畸形(17.0%)。影像学以椎体扁平及前端鸟嘴样突出(51.0%)、脊柱后凸(30.0%)、脊柱侧弯(29.0%)、肋骨飘带征(28.0%)、股骨头变形(10.0%)为主要特点。75.5%患者有尿黏多糖定性阳性,90.7%患者血N-乙酰半乳糖胺-6-硫酸酯酶(N acetylgalactosamine-6-sulfatase,GALNS)活性降低。本研究首次检出GALNS基因的5种新突变(p.Y190C、p.E192G、p.R259Y、p.A400P、c.898+2T>A),影响GALNS蛋白的折叠、分子间相互作用及合成,致GALNS合成减少,使得多组织中糖胺聚糖堆积。我国大样本MPSⅣA患者GALNS基因以错义及无义突变最常见,其中c.953T>G、c.706C>G、c.374C>T、c.1097T>C为高频突变。结论MPSⅣA是GALNS突变引起的罕见常染色体隐性遗传性溶酶体病。中国MPSⅣA患者以身材矮小、多部位骨骼畸形为主要表型,GALNS基因以错义及无义突变最常见,本研究首次发现GALNS的5种新突变,扩展了对MPSⅣA表型和致病基因突变谱的认识。

Objective To investigate the bone phenotypes and the pathogenic genetic mutations of patients with mucopolysaccharidosis typeⅣA(MPSⅣA).Methods Four patients from three families with abnormal gait and bone deformities were included.We investigated the clinical manifestations,bone turnover biomarkers,bone mineral density(BMD),skeletal radiographic features and MPS associated enzyme assay.Pathogenic mutations were identified by whole exome sequencing.We reviewed the literature about Chinese patients with MPSⅣA.Results The major manifestations of Chines MPSⅣA patients were short stature(74.0%),joint laxity(53.0%),pectus carinatum(39.0%),pectus excavatum(36.0%),genu varus/valgus(17.0%).The most common radiographic findings were flattening and anterior beaking of vertebral bodies(51.0%),kyphosis(30.0%),scoliosis(29.0%),flared rib(28.0%),and femoral heads deformity(10.0%).The urine mucopolysaccharides were positive in 75.5%patients and 90.7%patients had decreased GALNS activity.We identified five novel mutations of GALNS(p.Y190C,p.E192G,p.R259Y,p.A400P,c.898+2T>A)that affected the folding,intermolecular interactions,and reduced synthesis of GALNS,resulted in accumulation of glycosaminoglycans in multiple tissues.Missense/nonsense mutation of GALNS was the most common in Chinese MPSⅣA patients,of which c.953T>G,c.706C>G,c.374C>T,and c.1097T>C were the most common mutation.Conclusions MPSⅣA is a rare autosomal recessive hereditary lysosomal disease caused by GALNS mutations,with short stature and bone deformities as main characters of patients.Missense and nonsense mutations are the most common variants of GALNS.We identified five novel mutations of GALNS.This study extended the phenotypic and genetic spectrum of MPSⅣA.