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

BMC Medical Genetics

Niklas Dahl²  Shahid Mahmood Baig³  Raili Raininko¹  Tahir Naeem Khan³  Uzma Abdullah³  Syeda Seema Waseem³  Naveed Altaf Malik³  Abubakar Moawia³  Muhammad Tariq³  Joakim Klar²  Muhammad Jameel³ 

[1] Department of Radiology, Uppsala University, Uppsala 751 85, Sweden;Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala 751 08, Sweden;Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad 38000, Pakistan

关键词: Clinical variability;    Mutation;    AP4M1 gene;    AP-4 deficiency;    Cerebral palsy;   

Others  :  1090071
DOI  :  10.1186/s12881-014-0133-2

 received in 2014-06-30, accepted in 2014-12-03,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Jameel et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 3.

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