Alström Syndrome: Mutation Spectrum of ALMS1

Abstract

Alström Syndrome (ALMS), a recessive, monogenic ciliopathy caused by mutations in ALMS1, is typically characterized by multisystem involvement including early cone-rod retinal dystrophy and blindness, hearing loss, childhood obesity, type 2 diabetes mellitus, cardiomyopathy, fibrosis, and multiple organ failure. The precise function of ALMS1 remains elusive, but roles in endosomal and ciliary transport and cell cycle regulation have been shown. The aim of our study was to further define the spectrum of ALMS1 mutations in patients with clinical features of ALMS. Mutational analysis in a world-wide cohort of 204 families identified 109 novel mutations, extending the number of known ALMS1 mutations to 239 and highlighting the allelic heterogeneity of this disorder. This study represents the most comprehensive mutation analysis in patients with ALMS, identifying the largest number of novel mutations in a single study worldwide. Here, we also provide an overview of all ALMS1 mutations identified to date.

Keywords: ALMS1; Alström Syndrome; SNV; ciliopathy.

Figure 1

Novel ALMS1 mutations identified in this report and total previously reported. A. Exonic structure and location of novel ALMS1 mutations. B. Total number of reported substitution, deletion, insertion, and splice-site mutations per exon, including novel mutations and those previously reported in Supp. Table S1. Intronic regions where mutations of unknown significance, but predicted to alter splicing have been identified are shaded in dark gray.