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

• Published in: European journal of human genetics : EJHG Vol. 26; no. 5; pp. 745 - 748
• Main Authors: Tunca, Ceren, Akçimen, Fulya, Coşkun, Cemre, Gündoğdu-Eken, Aslı, Kocoglu, Cemile, Çevik, Betül, Bekircan-Kurt, Can Ebru, Tan, Ersin, Başak, A. Nazlı
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.05.2018; Springer International Publishing
• Subjects: Adolescent; Adult; Age; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - diagnosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - physiopathology; Brief Communication; Consanguinity; Endoplasmic reticulum; Exome Sequencing - methods; Female; Genetic Predisposition to Disease; Hereditary spastic paraplegia; Heredity; Humans; Hyperbilirubinemia; Hyperbilirubinemia - genetics; Hyperbilirubinemia - physiopathology; Life span; Male; Membrane Proteins - genetics; Middle Aged; Motor neuron diseases; Motor Neurons - pathology; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins - genetics; Mutation; Pedigree; Respiratory failure; Spastic Paraplegia, Hereditary - genetics; Spastic Paraplegia, Hereditary - physiopathology; Turkey; Turkey
• ISSN: 1018-4813; 1476-5438; 1476-5438
• DOI: 10.1038/s41431-018-0107-5

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.