A novel loss of function mutation in adaptor protein complex 4, subunit mu-1 causing autosomal recessive spastic...

Spastic paraplegia 50 (SPG50) is a rare autosomal recessive inherited disorder characterized by spasticity, severe intellectual disability and delayed or absent speech. Loss-of-function pathogenic mutations in the AP4M1 gene cause SPG50.

In this study, we investigated the clinical and genetic characteristics of a consanguineous family with two male siblings who had infantile hypotonia that progressed to spasticity, paraplegia in one and quadriplegia in the other patient. In addition, the patients also exhibited neurodevelopmental phenotypes including severe intellectual disability, developmental delay, microcephaly and dysmorphism.

In order to identify the genetic cause, we performed cytogenetics, whole-exome sequencing and Sanger sequencing. Whole-exome sequencing of the affected siblings and unaffected parents revealed a novel exonic frameshift insertion of eight nucleotides (c.341_342insTGAAGTGC) on exon 4 of the AP4M1 gene.

Insertion of these eight nucleotides in the AP4M1 gene is predicted to result in a premature protein product of 132 amino acids. The truncated protein product lacks a signal binding domain which is essential for protein-protein interactions and the transport of cargo proteins to the membrane. Thus, the identified variant is pathogenic and our study expands the knowledge of clinical and genetic features of SPG50.