An autosomal dominant ERLIN2 mutation leads to a pure HSP phenotype distinct from the autosomal recessive ERLIN2 mutations (SPG18)

Abstract

Hereditary spastic paraplegia (HSP) is a heterogeneous inherited disorder that manifests with lower extremity weakness and spasticity. HSP can be inherited by autosomal dominant, autosomal recessive, and X-linked inheritance patterns. Recent studies have shown that, although rare, mutations in a single gene can lead to multiple patterns of inheritance of HSP. We enrolled the HSP family showing autosomal dominant inheritance and performed genetic study to find the cause of phenotype in this family. We recruited five members of a Korean family as study participants. Four of the five family members had pure HSP. Part of the family members underwent whole-exome sequencing (WES) to identify the causative mutation. As the result of WES and Sanger sequencing analysis, a novel missense mutation (c.452 C > T, p.Ala151Val) of ERLIN2 gene was identified as the cause of the autosomal dominant HSP in the family. Our study suggests that the ERLIN2 gene leads to both autosomal recessive and autosomal dominant patterns of inheritance in HSP. Moreover, autosomal dominant HSP caused by ERLIN2 appears to cause pure HSP in contrast to autosomal recessive ERLIN2 related complicated HSP (SPG18).

Figure 1

Analysis of ERLIN2 mutation in a family. (A) The family pedigree is a three-generation pedigree with eight individual family members. The arrow indicates the proband and the asterisks indicate the individuals evaluated in this study. (B) Variants revealed by whole-exome sequencing of five family members were filtered out. The filtering strategy and the number of remaining variants at each step are shown. (C) The partial nucleotide sequences of exon 7 of ERLIN2 show the c.452 C > T mutation in the affected family members (II-2, III-1, III-2, IV-2). (D) Multiple alignments of the ERLIN2 partial region using CLC sequence viewer 6. Amino acid sequence of human ERLIN2 was aligned with that of other species. The asterisk represents amino acid position 151 in human ERLIN2.