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

Jin-Mo Park,Byeonghyeon Lee,Jong-Heun Kim,Un-Kyung Kim,Jinhoon Yu,Seong-Yong Park,Jin-Sung Park

doi:10.1038/s41598-020-60374-y

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).

Highlights

Hereditary spastic paraplegia (HSP) is a heterogeneous disease that manifests clinically as lower extremity weakness and spasticity
We describe an Asian family with pure autosomal dominant HSP caused by a novel ERLIN2 mutation that segregated among the family members
Pure or uncomplicated spastic paraplegia is characterized by progressive lower limb weakness and spasticity with minimal diminution of vibratory sense

Summary

Introduction

Hereditary spastic paraplegia (HSP) is a heterogeneous disease that manifests clinically as lower extremity weakness and spasticity. It is divided into two types, complicated and pure, and the complicated type shows additional neurological symptoms, such as ataxia, seizure, cognitive decline, extrapyramidal symptoms, and peripheral neuropathy[1]. More than 80 causal genes or loci have been identified and 75–80% of these are autosomal dominant, 25–30% are autosomal recessive, and 1–2% are X-linked[2]. A few studies have shown that mutations in Endoplasmic Reticulum Lipid Raft-Associated 2 (ERLIN2) gene cause autosomal recessive HSP and one recent study suggested that ERLIN2 causes autosomal dominant HSP in two unrelated Caucasian families[2,3]. We describe an Asian family with pure autosomal dominant HSP caused by a novel ERLIN2 mutation that segregated among the family members

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Results

Conclusion