Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome.-猫眼课题宝

DOI：

10.1016/j.ajhg.2014.10.014

发表时间：

2014-12

期刊：

American journal of human genetics

影响因子：

9.8

通讯作者：

中科院分区：

生物学1区

文献类型：

作者：

D. Wieczorek;W. Newman;T. Wieland;Tea Berulava;Maria Kaffe;D. Falkenstein;C. Beetz;E. Graf;T. Schwarzmayr;S. Douzgou;J. Clayton-Smith;Sarah B. Daly;S. Williams;S. Bhaskar;J. Urquhart;Beverley H Anderson;J. O’Sullivan;O. Boute;Jasmin Gundlach;J. Czeschik;A. V. van Essen;F. Hazan;Sarah S. Park;A. Hing;A. Kuechler;D. Lohmann;K. Ludwig;E. Mangold;L. Steenpass;M. Zeschnigk;J. Lemke;C. Lourenço;U. Hehr;E. Prott;M. Waldenberger;A. Böhmer;B. Horsthemke;R. O’Keefe;T. Meitinger;J. Burn;H. Lüdecke;T. Strom

主要剪接体成分的突变已在颅面异常疾病中得到描述，例如 Nager 综合征和 Guion-Almeida 型下颌面骨发育不全。由八个高度保守的蛋白质组成的 U5 剪接体复合物对于前 mRNA 剪接至关重要。我们在 Burn-McKeown 综合征 (BMKS) 患者中发现了 TXNL4A（该复合体的成员）的双等位基因突变。这种罕见疾病的特点是双侧后鼻孔闭锁、听力损失、唇裂和/或腭裂以及其他颅面畸形。 11 个受影响的家庭中有 9 个发现了突变。在 8 个家族中，受影响的个体在一个等位基因上携带罕见的功能丧失突变（无义、移码或微缺失），在另一个等位基因的核心启动子区域携带低频 34 bp 缺失（等位基因频率 0.76%）。在一个高度近亲的家庭中，之前被诊断为眼耳面部发育不良，四个受影响的个体是 34 bp 启动子缺失的纯合子，这与其他家庭中的启动子缺失不同。报告基因和体内测定表明，启动子缺失导致 TXNL4A 表达减少。酵母中 TXNL4A(Dib1) 的耗尽表明 tri-snRNP 复合物的组装减少。我们的结果表明 BMKS 是一种常染色体隐性病症，通常是由低频启动子缺失的复合杂合性与非常罕见的功能丧失突变相结合引起的。

Mutations in components of the major spliceosome have been described in disorders with craniofacial anomalies, e.g., Nager syndrome and mandibulofacial dysostosis type Guion-Almeida. The U5 spliceosomal complex of eight highly conserved proteins is critical for pre-mRNA splicing. We identified biallelic mutations inTXNL4A, a member of this complex, in individuals with Burn-McKeown syndrome (BMKS). This rare condition is characterized by bilateral choanal atresia, hearing loss, cleft lip and/or palate, and other craniofacial dysmorphisms. Mutations were found in 9 of 11 affected families. In 8 families, affected individuals carried a rare loss-of-function mutation (nonsense, frameshift, or microdeletion) on one allele and a low-frequency 34 bp deletion (allele frequency 0.76%) in the core promoter region on the other allele. In a single highly consanguineous family, formerly diagnosed as oculo-oto-facial dysplasia, the four affected individuals were homozygous for a 34 bp promoter deletion, which differed from the promoter deletion in the other families. Reporter gene and in vivo assays showed that the promoter deletions led to reduced expression ofTXNL4A. Depletion ofTXNL4A(Dib1) in yeast demonstrated reduced assembly of the tri-snRNP complex. Our results indicate that BMKS is an autosomal-recessive condition, which is frequently caused by compound heterozygosity of low-frequency promoter deletions in combination with very rare loss-of-function mutations.

Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome.

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