ITPR1 gene p.Val1553Met mutation in Russian family with mild Spinocerebellar ataxia

Abstract

BackgroundSpinocerebellar ataxias (SСAs) are a highly heterogeneous group of inherited neurological disorders. The symptoms of ataxia vary in individual patients and even within the same SCA subtype. A study of a four-generation family with autosomal dominant (AD) non-progressive SCA with mild symptoms was conducted. The genotyping of this family revealed no frequent pathogenic mutations. So the objective of this study was to identify the genetic causes of the disease in this family with the technology of whole-exome sequencing (WES).Methods and resultsWES, candidate variant analysis with further Sanger sequencing, mRNA secondary structure prediction, and RSCU analysis were performed; a heterozygous missense mutation in ITPR1 was identified.ConclusionOur study confirms the fact that ITPR1 gene plays a certain role in the pathogenesis of SCAs, and, therefore, we suggest that c.4657G>A p.Val1553Met) is a disease-causing mutation in the family studied.

Inositol 1,4,5-Trisphosphate Receptor Mutations Associated with Human Disease

“…Though all members of the Australian family with the V1553M mutation exhibited intellectual disability, five affected individuals in a four generation Russian family with the same mutation did not (Shadrina et al, 2016, Dudding et al, 2004, Huang et al, 2012). Additionally, whereas amelioration of symptoms was reported in the Australian family, at least one individual in the Russian family reported a mild increase in gait and speech difficulties over time (Shadrina et al, 2016, Dudding et al, 2004, Huang et al, 2012). Worsening of symptoms, despite remaining clinically non-progressive, was also observed in one individual who expressed the IP 3 R1 splice mutation in exon 14 and developed balance problems after 10 years of age (Wang et al, 2017).…”

IP3 receptor mutations and brain diseases in human and rodents

“…The V1553M mutation has also been reported in a Russian family (Shadrina et al . ). Although the Ca 2+ release properties of the mutants have not yet been analyzed, both the residues are highly conserved among vertebrates and are located within the critical domains for ITPR1 function.…”

“…Huang et al reported two missense mutations in the families of patients with SCA29 (Huang et al 2012): V1553M in an Australian family and N602D in a Canadian family. The V1553M mutation has also been reported in a Russian family (Shadrina et al 2016). Although the Ca 2+ release properties of the mutants have not yet been analyzed, both the residues are highly conserved among vertebrates and are located within the critical domains for ITPR1 function.…”

A missense variant in ITPR1 provides evidence for autosomal recessive SCA29 with asymptomatic cerebellar hypoplasia in carriers

“…[12][13][14] Magnetic resonance imaging (MRI) of both clinical forms demonstrates cerebellar atrophy, often prominent and mainly affecting the vermis. 9,10,13,15 More recently, patients with cerebellar syndrome, intellectual disability and aniridia (Gillespie syndrome) were added to the ITPR1-associated phenotypes. 14,16 Taken together, the spectrum of ITPR1-associated phenotypes is intriguing.…”

“…In contrast, cases with a congenital or infantile onset of SCA29 appear to be caused exclusively by monoallelic ITPR1 gene variants that alter the structure of IP3R1, presumably through a dominant negative effect. 12,[14][15][16][17][18] To date, no autosomal recessive form of SCA29 has been attributed to ITPR1 variants.…”