ALMS1 and Alström syndrome: a recessive form of metabolic, neurosensory and cardiac deficits

Abstract

Alström syndrome (AS) is characterised by metabolic deficits, retinal dystrophy, sensorineural hearing loss, dilated cardiomyopathy and multi-organ fibrosis. Elucidating the function of the mutated gene, ALMS1, is critical for the development of specific treatments and may uncover pathways relevant to a range of other disorders including common forms of obesity and type 2 diabetes. Interest in ALMS1 is heightened by the recent discovery of its involvement in neonatal cardiomyocyte cell cycle arrest, a process with potential relevance to regenerative medicine. ALMS1 encodes a ~ 0.5 megadalton protein that localises to the base of centrioles. Some studies have suggested a role for this protein in maintaining centriole-nucleated sensory organelles termed primary cilia, and AS is now considered to belong to the growing class of human genetic disorders linked to ciliary dysfunction (ciliopathies). However, mechanistic details are lacking, and recent studies have implicated ALMS1 in several processes including endosomal trafficking, actin organisation, maintenance of centrosome cohesion and transcription. In line with a more complex picture, multiple isoforms of the protein likely exist and non-centrosomal sites of localisation have been reported. This review outlines the evidence for both ciliary and extra-ciliary functions of ALMS1.

Cardiac regeneration and remodelling of the cardiomyocyte cytoarchitecture

“…Patients with this ciliopathy show persisting postnatal CM proliferation, a phenotype that can be reproduced in homozygous mutant mice and anti‐ALMS1 siRNA‐treated cultured CMs; in normal conditions, expression of the protein increases during terminal differentiation of neonatal CMs . Thus, ALMS1 appears to act as a suppressor of CM proliferation .…”

“…Several observations link the biological events occurring at the centrosome and the primary cilium to the regulation of CM proliferation. First, biallelic mutations in the giant protein Alstrom syndrome 1 (ALMS1), which is broadly expressed in most cell types and localizes to the proximal end of the centrioles , cause a form of rare cardiomyopathy characterized by delayed cell cycle arrest of neonatal CMs . Patients with this ciliopathy show persisting postnatal CM proliferation, a phenotype that can be reproduced in homozygous mutant mice and anti‐ALMS1 siRNA‐treated cultured CMs; in normal conditions, expression of the protein increases during terminal differentiation of neonatal CMs .…”

Isoform-specific aPKC renders primary cilia dispensable for Hedgehog signaling and basal cell carcinoma growth

“…PTCH1, a negative suppressor of the HH pathway that is mutated in ~70% of human BCC (Bonilla et al 2016), is highly mutated as expected. ALMS1, which encodes a centrosomal protein mutated in Alström syndrome (Hearn 2019), is the most highly mutated gene in SMO antagonist-resistant BCC. Interestingly, four Usher syndromerelated genes, which are a major cause of deaf-blindness in humans (Géléoc and El-Amraoui, 2020), are overrepresented in the top 11 most mutated genes.…”

High Prevalence Mutations in ALMS1 in Spanish Alström Patients

“…The prevalence of symptoms like DMC, hepatic dysfunction or hearing loss seems to be conditioned by other unknown agents. Numerous candidate ALMS1-interacting proteins have been reported, that could play a modulating function 22 Until now, the exactly role of ALMS1 protein it is no clear, and has been detected in other tissues although the basal body location 22 . As pointed out by Braine 2017, some protein isoforms might have distinct intracellular locations and may perform different functions.…”

“…beyond the ciliary function 23 . ALMS1 have been related with several cellular processes including endosomal tra cking, actin organisation and transcription, neuronal migration, maintenance of cellular quiescence, adipogenesis, spermatogenesis, maintenance of pancreatic β cell mass, adaptive thermogenesis, cell cycle arrest of cardiomyocytes and regulation of blood pressure and renal function 22,23 .…”