A novel AP4M1 mutation in autosomal recessive cerebral palsy syndrome and clinical expansion of AP-4 deficiency

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• 作者：Muhammad Jameel (1)
  Joakim Klar (2)
  Muhammad Tariq (1)
  Abubakar Moawia (1)
  Naveed Altaf Malik (1)
  Syeda Seema Waseem (1)
  Uzma Abdullah (1)
  Tahir Naeem Khan (1)
  Raili Raininko (3)
  Shahid Mahmood Baig (1)
  Niklas Dahl (2)
  
  1. Human Molecular Genetics Laboratory ; National Institute for Biotechnology and Genetic Engineering (NIBGE) ; PIEAS ; Faisalabad ; 38000 ; Pakistan
  2. Department of Immunology ; Genetics and Pathology ; Science for Life Laboratory ; Uppsala University ; Uppsala ; 751 08 ; Sweden
  3. Department of Radiology ; Uppsala University ; Uppsala ; 751 85 ; Sweden
  
• 关键词：Cerebral palsy ; AP ; 4 deficiency ; AP4M1 gene ; Mutation ; Clinical variability
• 刊名：BMC Medical Genetics
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：15
• 期：1
• 全文大小：712 KB
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• 刊物主题：Human Genetics; Genetics and Population Dynamics;
• 出版者：BioMed Central
• ISSN：1471-2350

文摘

Background 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. Methods 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. Results 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. Conclusion 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.