A novel AP4M1 mutation in autosomal recessive cerebral palsy syndrome and clinical expansion of AP-4 deficiency.
A novel AP4M1 mutation in autosomal recessive cerebral palsy syndrome and clinical expansion of AP-4 deficiency.
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DOI：
10.1186/s12881-014-0133-2
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发表时间：
2014-12-14
影响因子：
--
通讯作者：
Dahl N
中科院分区：
文献类型：
--
作者：
Jameel M;Klar J;Tariq M;Moawia A;Altaf Malik N;Seema Waseem S;Abdullah U;Naeem Khan T;Raininko R;Baig SM;Dahl N
脑性瘫痪（CP）是一种异质性神经发育障碍，与三分之一的病例中的智力残疾相关。最近的研究结果支持孟德尔遗传在亚组患者的疾病。本研究的目的是确定一个新的遗传原因，截瘫CP与智力残疾的近亲巴基斯坦家庭。我们对两个患有CP和智力残疾的兄弟进行了全外显子组测序（WES）。使用定量实时PCR对来自培养的成纤维细胞的总RNA进行AP 4 M1 mRNA分析。对这对兄弟进行了临床和MRI研究。我们在受影响的兄弟中发现了一种新的纯合子AP 4 M1突变c.194_195delAT，p.Y65Ffs*50。定量RT-PCR分析显示AP 4 M1 mRNA水平显著降低，表明部分无义介导的mRNA衰减。一些临床和MRI特征与AP-4复合物缺乏一致。然而，与先前报道的AP 4 M1突变病例相反，我们的患者表现出攻击性行为和相对较晚的疾病发作。这项研究表明，除了轻度畸形特征、智力残疾、痉挛性下肢轻瘫和头围缩小外，AP 4 M1突变还与攻击性行为相关。我们的发现扩展了与AP-4复合物缺乏相关的临床谱，该研究说明了MRI和WES在诊断CP和智力残疾患者中的重要性。
Cerebral palsy (CP) is a heterogeneous neurodevelopmental disorder associated with intellectual disability in one-third of cases. Recent findings support Mendelian inheritance in subgroups of patients with the disease. The purpose of this study was to identify a novel genetic cause of paraplegic CP with intellectual disability in a consanguineous Pakistani family. We performed whole-exome sequencing (WES) in two brothers with CP and intellectual disability. Analysis of AP4M1 mRNA was performed using quantitative real-time PCR on total RNA from cultured fibroblasts. The brothers were investigated clinically and by MRI. We identified a novel homozygous AP4M1 mutation c.194_195delAT, p.Y65Ffs*50 in the affected brothers. Quantitative RT-PCR analysis showed markedly reduced AP4M1 mRNA levels suggesting partial non-sense mediated mRNA decay. Several clinical and MRI features were consistent with AP-4 complex deficiency. However, in contrast to previously reported cases with AP4M1 mutations our patients show an aggressive behavior and a relatively late onset of disease. This study shows an AP4M1 mutation associated with aggressive behavior in addition to mild dysmorphic features, intellectual disability, spastic paraparesis and reduced head circumference. Our findings expand the clinical spectrum associated with AP-4 complex deficiency and the study illustrates the importance of MRI and WES in the diagnosis of patients with CP and intellectual disability.
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影响因子：
9.8
作者：
Clark, SL;Hankins, GDV
通讯作者：
Hankins, GDV
影响因子：
1.9
作者：
Costeff, H
通讯作者：
Costeff, H
影响因子：
2.9
作者：
Matsuda, Shinji;Yuzaki, Michisuke
通讯作者：
Yuzaki, Michisuke
DOI：
10.1002/ajmg.1320370311
发表时间：
1990-11-01
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
PETTERSON, B;STANLEY, F;HENDERSON, D
通讯作者：
HENDERSON, D
影响因子：
4
作者：
Moreno-De-Luca A;Helmers SL;Mao H;Burns TG;Melton AM;Schmidt KR;Fernhoff PM;Ledbetter DH;Martin CL
通讯作者：
Martin CL