Two Novel Homozygous SACS Mutations in Unrelated Patients Including the First Reported Case of Paternal UPD as an Etiologic Cause of ARSACS

Abstract

Autosomal recessive spastic ataxia of Charlevoix-Saguenay, more commonly known as ARSACS, is an early-onset cerebellar ataxia with spasticity, amyotrophy, nystagmus, dysarthria, and peripheral neuropathy. SACS is the only gene known to be associated with the ARSACS phenotype. To date, 55 mutations have been reported; of these, only five in Italian patients. We found two novel homozygous nonsense mutations in the giant exon of SACS gene in two unrelated patients with classical ARSACS phenotype. Characterization of the homozygous nature of the mutations through genotyping of the parents, quantitative DNA analysis and indirect STS studies permitted us to confirm in one of the cases that uniparental isodisomy of the paternal chromosome 13 carrying the mutated SACS gene played an etiologic role in the disease.

A Novel Homozygous <b><i>SACS</i></b> Mutation Identified by Whole-Exome Sequencing in a Consanguineous Family with Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

“…Damages in either of these 2 domains would be deleterious for the function of the sacsin protein. Consistent with this idea, several mutations downstream of this site (NP_055178: p.F3166Tfs * 9) have previously been identified in ARSACS worldwide [Anesi et al, 2011;Pilliod et al, 2015].…”

New findings in the ataxia of Charlevoix–Saguenay

“…The nine exons consist of over 15.000 bp and encode sacsin, a 4.579 amino acid protein [39,40]. This contains an N-terminus ubiquitin-like (UbL) domain (amino acids 1-124), able to interact with the proteasome [30], a J domain (which is the defining feature of the Hsp40 family of Hsp70 co-chaperones) between amino acids 4322-4370, and a C-terminus HEPN domain involved in nucleotide binding, between residues 4,451 and 4,567 [4]. Sacsin also contains an N-terminus recurring arrangement of three adjacent 360 amino acid domains, which has been termed ''sacsin repeating region''.…”

“…Patient 1 exhibited the hemizygous mutation c.13405G [ C/p.A4469P, which replaces alanine 4469 for proline in the functionally relevant HEPN domain [4]. The other allele, inherited from her mother, harboured a large genomic deletion (D) that encompassed SACS, as described elsewhere [38].…”

Co-occurrence of recurrent duplications of the DiGeorge syndrome region on both chromosome 22 homologues due to inherited and de novo events

“…Patients with identical mutations on both the paternal and maternal alleles, i.e. homozygous mutations, leading to pathological manifestations of autosomal recessive diseases, with only one parent is a heterozygous carrier, have been previously reported 23 24. Uniparental isodisomy (UPD) is frequently responsible for this observation.…”