ERLIN1 mutations cause teenage-onset slowly progressive ALS in a large Turkish pedigree

Eur J Hum Genet. 2018 May;26(5):745-748. doi: 10.1038/s41431-018-0107-5. Epub 2018 Feb 16.

Abstract

Amyotrophic lateral sclerosis (ALS) is a late-onset motor neuron disease with mostly dominant inheritance and a life expectancy of 2-5 years; however, a quite common occurrence of atypical forms of the disease, due to recessive inheritance, has become evident with the use of NGS technologies. In this paper, we describe a family with close consanguinity for at least four generations, suffering from a slowly progressive form of ALS. Spastic walking is observed since teenage years, while bulbar symptoms start much later, at the fifth or sixth decade of life. Patients usually die because of respiratory failure. Using whole-exome sequencing, we identified a novel homozygous p.(Val94Ala) (c.281T>C) (NG_052910.1) (NM_006459) variation in the endoplasmic reticulum lipid raft associated protein 1 (ERLIN1) gene, which segregates with the disease in the family. Here we suggest that ERLIN1 variants, previously shown in juvenile hereditary spastic paraplegia cases, may also be the cause of a slowly progressive early-onset ALS, starting with upper motor neuron features and developing into classical ALS with the addition of lower motor neuron dysfunction. We also demonstrate that ATP-binding cassette subfamily C member 2 (ABCC2) gene, responsible for hyperbilirubinemia, is linked to ERLIN1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amyotrophic Lateral Sclerosis / diagnosis
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / physiopathology
  • Consanguinity
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Hyperbilirubinemia / genetics
  • Hyperbilirubinemia / physiopathology
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Motor Neurons / pathology
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins / genetics*
  • Mutation
  • Pedigree
  • Spastic Paraplegia, Hereditary / genetics
  • Spastic Paraplegia, Hereditary / physiopathology
  • Turkey
  • Whole Exome Sequencing / methods*

Substances

  • ABCC2 protein, human
  • ERLIN2 protein, human
  • Membrane Proteins
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins