Duerinckx Sarah, Verhelst Helene, Perazzolo Camille, David Philippe, Desmyter Laurence, Pirson Isabelle, Abramowicz Marc
IRIBHM, Université Libre de Bruxelles, Brussels, Belgium.
Department of Paediatric Neurology, Ghent University Hospital, Ghent, Belgium.
BMC Med Genet. 2017 May 2;18(1):48. doi: 10.1186/s12881-017-0412-9.
Autosomal recessive defects of either the B1, E1, M1 or S1 subunit of the Adaptor Protein complex-4 (AP4) are characterized by developmental delay, severe intellectual disability, spasticity, and occasionally mild to moderate microcephaly of essentially postnatal onset.
We report on a patient with severe microcephaly of prenatal onset, and progressive spasticity, developmental delay, and severe intellectual deficiency. Exome sequencing showed a homozygous mutation in AP4M1, causing the replacement of an arginine by a stop codon at position 338 of the protein (p.Arg338X). The premature stop codon truncates the Mu homology domain of AP4M1, with predicted loss of function. Exome analysis also showed heterozygous variants in three genes, ATR, MCPH1 and BLM, which are known causes of autosomal recessive primary microcephaly.
Our findings expand the AP4M1 phenotype to severe microcephaly of prenatal onset, and more generally suggest that the AP4 defect might share mechanisms of prenatal neuronal depletion with other genetic defects of brain development causing congenital, primary microcephaly.
衔接蛋白复合体4(AP4)的B1、E1、M1或S1亚基的常染色体隐性缺陷的特征为发育迟缓、严重智力残疾、痉挛,偶尔在出生后出现轻度至中度小头畸形。
我们报告了一名产前出现严重小头畸形、进行性痉挛、发育迟缓及严重智力缺陷的患者。外显子组测序显示AP4M1存在纯合突变,导致该蛋白第338位的精氨酸被终止密码子取代(p.Arg338X)。该过早终止密码子截断了AP4M1的Mu同源结构域,预测其功能丧失。外显子组分析还显示三个基因ATR、MCPH1和BLM存在杂合变异,这些基因是常染色体隐性原发性小头畸形的已知病因。
我们的研究结果将AP4M1表型扩展至产前严重小头畸形,更普遍地表明,AP4缺陷可能与导致先天性原发性小头畸形的其他脑发育基因缺陷共享产前神经元耗竭机制。