A novel CISD2 intragenic deletion, optic neuropathy and platelet aggregation defect in Wolfram syndrome type 2

Abstract

BackgroundWolfram Syndrome type 2 (WFS2) is considered a phenotypic and genotypic variant of WFS, whose minimal criteria for diagnosis are diabetes mellitus and optic atrophy. The disease gene for WFS2 is CISD2. The clinical phenotype of WFS2 differs from WFS1 for the absence of diabetes insipidus and psychiatric disorders, and for the presence of bleeding upper intestinal ulcers and defective platelet aggregation. After the first report of consanguineous Jordanian patients, no further cases of WFS2 have been reported worldwide. We describe the first Caucasian patient affected by WFS2.Case presentationThe proband was a 17 year-old girl. She presented diabetes mellitus, optic neuropathy, intestinal ulcers, sensorineural hearing loss, and defective platelet aggregation to ADP. Genetic testing showed a novel homozygous intragenic deletion of CISD2 in the proband. Her brother and parents carried the heterozygous mutation and were apparently healthy, although they showed subclinical defective platelet aggregation. Long runs of homozygosity analysis from SNP-array data did not show any degree of parental relationship, but the microsatellite analysis confirmed the hypothesis of a common ancestor.ConclusionOur patient does not show optic atrophy, one of the main diagnostic criteria for WFS, but optic neuropathy. Since the “asymptomatic” optic atrophy described in Jordanian patients is not completely supported, we could suppose that the ocular pathology in Jordanian patients was probably optic neuropathy and not optic atrophy. Therefore, as optic atrophy is required as main diagnostic criteria of WFS, it might be that the so-called WFS2 could not be a subtype of WFS. In addition, we found an impaired aggregation to ADP and not to collagen as previously reported, thus it is possible that different experimental conditions or inter-patient variability can explain different results in platelet aggregation. Further clinical reports are necessary to better define the clinical spectrum of this syndrome and to re-evaluate its classification.

Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia

“…Pathogenic variants in the CISD2 gene (MIM# 611507) have been identified in patients with WS type 2 (Amr et al., ; Mozzillo et al., ). WS type 2 differs from type 1 in respect that so far no diabetes insipidus (DI) and psychiatric disorder has been associated with the disease, and the novel presence of defective platelet aggregation leading to peptic ulcer bleeding.…”

“…Studies in mice show that cisd2 deficiency in these animals causes mitochondrial death and dysfunction accompanied by autophagic death (Chen et al., ). To date, only 13 individuals with CISD2 mutations have been reported in the literature (Amr et al., ; Mozzillo et al., ; Rondinelli, Novara, Calcaterra, Zuffardi, & Genovese, ).…”

“…The variant caused missense changes in a conserved amino acid as well as aberrant splicing resulting in the deletion of exon 2. Recently, two CISD2 mutations have been identified in patients of Italian origin, the c.(103+1_104‐1)_(318+1_319‐1)del and the c.103+1G>A, causing deletions of exon 2 and exon 1, respectively (Mozzillo et al., ; Rondinelli et al., ). The exon 2 deletion of CISD2 is predicted to abolish the transmembrane domain of the protein.…”

Clinical utility gene card for: Wolfram syndrome

“…Reported variants include a missense mutation in Jordanian families suggestive of a founder event and a deletion in one non-consanguineous Italian family. [2][3][4] There has been a suggested link between mitochondrial DNA mutations and WFS. 5 A 7.6-kb heteroplasmic deletion (spanning nucleotides 6465-14135) has been reported, 6 in addition to multiple deletions of mitochondrial DNA and a point mutation (m.3337G4A) in the mitochondrial gene encoding subunit ND1 in a Tunisian patient.…”

Diabetes mellitus y atrofia óptica: estudio del síndrome de Wolfram

“…Las proteínas no plegadas o mal plegadas tienen un efecto deletéreo en la función celular y pueden causar su muerte, proceso al que se conoce como proteotoxicidad o estrés del RE 10,[12][13][14][15] . Para mantener la homeostasis del RE, las células han desarrollado un mecanismo adaptativo de respuesta al estrés, llamado respuesta a proteínas desplegadas, o UPR por sus siglas en inglés (Unfolded Protein Response), que comprende un conjunto de vías de señalización intracelular para hacer frente al estrés metabólico, oxidativo e inflamatorio 10,16,17 . La UPR tiene la capacidad de actuar como un switch binario entre la vida y la muerte, pues puede regular tanto los efectores de supervivencia como los apoptó-ticos 18 .…”