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

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.

Fig. 1

Pedigree of the family with ERLIN1 variation. The double lines between spouses indicate consanguinity. Segregation of the identified variations E₁ (ERLIN1 c.281T>C, p.(Val94Ala), NM_006459) and E₂ (ABCC2 c.2714G>T, p.(Arg905Ile), NM_000392) are designated. The individual IDs in the pedigree (e.g., ALS 518) are laboratory internal IDs, do not designate any phenotype, and are for the purpose of finding individuals in the LOVD webpage. * shows the individuals subjected to whole-exome sequencing analysis. AO age of onset, b date of birth, d date of death

Fig. 2

The conservation of the valine residue at position 94 (in bold) of ERLIN1 protein among 10 species