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Biallelic variants in EFEMP1 in a man with a pronounced connective tissue phenotype.
European Journal of Human Genetics ( IF 5.2 ) Pub Date : 2019-12-02 , DOI: 10.1038/s41431-019-0546-7
Sean G W Driver 1 , Meremaihi R Jackson 1 , Konrad Richter 2 , Paul Tomlinson 3 , Ben Brockway 4 , Benjamin J Halliday 1 , David M Markie 5 , Stephen P Robertson 1 , Emma M Wade 1
Affiliation  

Connective tissue disorders are a spectrum of diseases that affect the integrity of tissues including skin, vasculature, and joints. They are often caused by variants that disrupt genes encoding components of extracellular matrix (ECM). The fibulin glycoproteins are ECM proteins important for integrity of tissues including dermis, retina, fascia, and vasculature. The fibulin family consists of seven members (fibulins-1 to -7) and is defined by a fibulin-type domain at the C-terminus. The family is associated with human diseases, for instance a variant in FBLN1, encoding fibulin-1, is associated with synpolydactyly, while one in EFEMP1, encoding fibulin-3, causes Doyne honeycomb degeneration of the retina. Loss-of-function of fibulins-4 and -5 causes cutis laxa, while variants in fibulins-5 and -6 are associated with age-related macular degeneration. Of note, EFEMP1 is not currently associated with any connective tissue disorder. Here we show biallelic loss-of-function variants in EFEMP1 in an individual with multiple and recurrent abdominal and thoracic herniae, myopia, hypermobile joints, scoliosis, and thin translucent skin. Fibroblasts from this individual express significantly lower EFEMP1 transcript than age-matched control cells. A skin biopsy, visualised using light microscopy, showed normal structure and abundance of elastic fibres. The phenotype of this individual is remarkably similar to the Efemp1 knockout mouse model that displays multiple herniae with premature aging and scoliosis. We conclude that loss of EFEMP1 function in this individual is the cause of a connective tissue disorder with a novel combination of phenotypic features, and can perhaps explain similar, previously reported cases in the literature.



中文翻译:

具有明显结缔组织表型的男性 EFEMP1 中的双等位基因变异。

结缔组织疾病是一系列影响组织完整性的疾病,包括皮肤、脉管系统和关节。它们通常是由破坏编码细胞外基质 (ECM) 成分的基因的变异引起的。纤维蛋白糖蛋白是对包括真皮、视网膜、筋膜和脉管系统在内的组织的完整性很重要的 ECM 蛋白。fibulin 家族由 7 个成员(fibulins-1 到 -7)组成,由 C 端的 fibulin 型结构域定义。该家族与人类疾病有关,例如FBLN1中的一个变体,编码 fibulin-1,与多指畸形有关,而 EFEMP1 中的一个变体,编码fibulin-3,导致视网膜的Doyne蜂窝状变性。fibulins-4 和 -5 的功能丧失会导致皮肤松弛,而 fibulins-5 和 -6 的变异与年龄相关性黄斑变性有关。值得注意的是,EFEMP1目前与任何结缔组织疾病无关。在这里,我们展示了EFEMP1双等位基因功能丧失变异体在患有多发性和复发性腹和胸疝、近视、关节活动过度、脊柱侧弯和薄半透明皮肤的个体中。该个体的成纤维细胞表达显着降低的EFEMP1转录本高于年龄匹配的对照细胞。使用光学显微镜观察的皮肤活检显示正常结构和丰富的弹性纤维。该个体的表型与Efemp1敲除小鼠模型非常相似,该模型显示多发疝气伴早衰和脊柱侧凸。我们得出结论,该个体中EFEMP1功能的丧失是结缔组织疾病的原因,具有新的表型特征组合,并且可能可以解释文献中先前报道的类似病例。

更新日期:2019-12-02
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