Mutations in FKBP14 Cause a Variant of Ehlers-Danlos Syndrome with Progressive Kyphoscoliosis, Myopathy, and Hearing Loss
Mutations in FKBP14 Cause a Variant of Ehlers-Danlos Syndrome with Progressive Kyphoscoliosis, Myopathy, and Hearing Loss
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DOI：
10.1016/j.ajhg.2011.12.004
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发表时间：
2012-02-10
影响因子：
9.8
通讯作者：
Fauth, Christine
中科院分区：
文献类型：
--
作者：
Baumann, Matthias;Giunta, Cecilia;Fauth, Christine
我们报告了一种常染色体隐性变异的埃勒斯-当洛斯综合征（EDS），其特征是出生时严重的肌肉张力减退、进行性脊柱侧凸、关节过度活动、皮肤超弹性、肌病、感觉神经性听力障碍和尿中正常的吡啶啉排泄。临床上，这种疾病与脊柱后凸型EDS（EDS VIA）和乌尔里希先天性肌营养不良症有许多共同特征。在一个大的蒂罗尔族的连锁分析确定了一个纯合移码突变FKBP 14在两个受影响的个人。基于该疾病的主要临床特征，鉴定了来自不同欧洲国家的另外4名携带FKBP 14纯合或复合杂合突变的个体。FKBP 14属于FK 506结合肽基脯氨酰顺反异构酶（PPlases）家族。ER-居民FKBP已被建议作为折叠催化剂，通过加速肽基脯氨酰键的顺反异构化，偶尔也作为伴侣。我们证明，FKBP 14是本地化的内质网（ER）和FKBP 14的缺乏导致扩大ER cisplasmic在真皮成纤维细胞在体内。此外，FKBP 14缺陷的成纤维细胞的间接免疫荧光指示细胞外基质在体外的改变的组装。这些发现表明，ER中的蛋白质折叠的干扰影响细胞外基质的一个或多个组件可能会导致在这种疾病的广义结缔组织参与。FKBP 14突变分析应考虑在所有明显脊柱后凸型EDS和尿吡啶啉排泄正常的个体，特别是与感音神经性听力障碍。
We report on an autosomal-recessive variant of Ehlers-Danlos syndrome (EDS) characterized by severe muscle hypotonia at birth, progressive scoliosis, joint hypermobility, hyperelastic skin, myopathy, sensorineural hearing impairment, and normal pyridinoline excretion in urine. Clinically, the disorder shares many features with the kyphoscoliotic type of EDS (EDS VIA) and Ullrich congenital muscular dystrophy. Linkage analysis in a large Tyrolean kindred identified a homozygous frameshift mutation in FKBP14 in two affected individuals. Based on the cardinal clinical characteristics of the disorder, four additional individuals originating from different European countries were identified who carried either homozygous or compound heterozygous mutations in FKBP14. FKBP14 belongs to the family of FK506-binding peptidyl-prolyl cis-trans isomerases (PPlases). ER-resident FKBPs have been suggested to act as folding catalysts by accelerating cis-trans isomerization of peptidyl-prolyl bonds and to act occasionally also as chaperones. We demonstrate that FKBP14 is localized in the endoplasmic reticulum (ER) and that deficiency of FKBP14 leads to enlarged ER cisterns in dermal fibroblasts in vivo. Furthermore, indirect immunofluorescence of FKBP14-deficient fibroblasts indicated an altered assembly of the extracellular matrix in vitro. These findings suggest that a disturbance of protein folding in the ER affecting one or more components of the extracellular matrix might cause the generalized connective tissue involvement in this disorder. FKBP14 mutation analysis should be considered in all individuals with apparent kyphoscoliotic type of EDS and normal urinary pyridinoline excretion, in particular in conjunction with sensorineural hearing impairment.