Genetic analysis of SS18L1 in French amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease including about 15% of genetically determined forms. A de novo mutation in the SS18L1 (also known as CREST or KIAA0693) gene encoding the calcium-responsive transactivator and/or neuronal chromatin remodeling complex subunit has recently been identified by exome sequencing of 47 sporadic ALS trios. This Q388stop mutation deleting the last 9 amino acids was shown to impair activity-dependent dendritic outgrowth. A missense mutation (c.369T>G, p.Ileu123Met) was also found in 1 of 62 ALS families previously screened for other ALS-related genes and not carrying any mutation. To confirm the contribution of SS18L1 to ALS, we sequenced the 11 coding exons and exon-intron boundaries in 87 familial ALS (FALS). We identified 2 variants: the c.660_668del, p.Gln222_Ser224del in a patient devoid of mutation in any ALS related genes and the c.790G>A, p.Ala264Thr in a patient carrying a p.Arg96Leu variant in the OPTN gene. As these variants were not found in databases and were absent from 180 controls they could be new SS18L1 mutations causing ALS.

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