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Wolfram syndrome 2 (WFS2) is a rare autosomal recessive neurodegenerative disorder defined by early-onset non–insipidus diabetes mellitus and progressive optic neuropathy, often accompanied by peptic ulcer disease and defective platelet aggregation. The disease is caused by biallelic loss-of-function variants in CISD2, encoding the ER‐localized 2Fe‐2S protein Miner1 (NAF-1) (PMID:25056293; PMID:29237418; PMID:28335035).
Autosomal recessive CISD2 mutations have been identified in five unrelated probands across four families, each presenting with diabetes mellitus and optic neuropathy or atrophy, alongside impaired platelet aggregation ([PMID:25056293]; [PMID:29237418]; [PMID:28335035]; [PMID:31309279]; [PMID:17846994]). Segregation analysis in consanguineous and non‐consanguineous pedigrees confirms recessive inheritance, with heterozygous relatives asymptomatic but demonstrating subclinical aggregation defects. Based on this consistent genetic and phenotypic evidence, the CISD2–WFS2 association reaches a Strong ClinGen clinical validity classification.
Inheritance is autosomal recessive. Reported variants include homozygous intragenic deletions, splice‐site mutations (e.g., c.103+1G>A), and missense changes. One illustrative variant is c.215A>G (p.Asn72Ser), identified homozygously in a Moroccan patient, disrupting CISD2 function and recapitulating WFS2 clinical features ([PMID:28335035]). In total, five probands harbor two missense, one splice‐site, one deletion, and one novel missense variant (c.310T>C (p.Ser104Pro)) spectrum. No recurrent or founder alleles have been established. Genetic evidence is graded Moderate by ClinGen criteria, reflecting identification of multiple variant classes across unrelated cases.
Functional studies robustly support a loss-of-function mechanism. Patient-derived fibroblasts with c.215A>G show enhanced ER-to-mitochondrial Ca²⁺ flux, cytosolic Ca²⁺ overload, and altered mitochondrial dynamics without overt ER stress ([PMID:28335035]). Structural characterization of Miner1 reveals a homodimeric 2Fe–2S cluster–binding NEET fold essential for redox regulation ([PMID:19580816]). CISD2 knockout mice exhibit premature aging phenotypes, blindness, muscle atrophy, and shortened lifespan, mirroring multisystem features of WFS2 ([PMID:24974737]). These concordant cellular, biochemical, and animal model data merit Strong functional evidence.
Biallelic CISD2 variants cause WFS2 through haploinsufficiency of the redox-active Miner1, leading to ER–mitochondrial Ca²⁺ dysregulation and multisystem degeneration. The definitive autosomal recessive inheritance, multiple variant classes, segregation data, and mechanistic studies underpin a Strong gene–disease association. Early molecular diagnosis of CISD2 variants informs prognosis, guides monitoring for ulceration and aggregation defects, and enables genetic counselling.
Key Take-home: CISD2 testing should be included in diagnostic panels for early-onset diabetes with optic neuropathy and platelet dysfunction, as timely recognition of WFS2 has direct implications for patient management.
Gene–Disease AssociationStrongFive unrelated probands across four families with consistent autosomal recessive segregation and concordant functional studies. Genetic EvidenceModerateIdentification of loss-of-function deletion, splice-site, and missense variants in 5 probands; segregation in consanguineous families; variant spectrum includes 2 missense, 1 splice, 1 intragenic deletion. Functional EvidenceStrongMultiple studies demonstrate haploinsufficiency mechanism with loss of 2Fe-2S functionality, ER-mitochondrial Ca2+ dysregulation in patient cells, and Cisd2 knockout mouse recapitulates phenotype. |