CISD2 – Wolfram syndrome

CISD2 (CDGSH iron sulfur domain 2) is implicated in autosomal recessive Wolfram syndrome, a progressive neurodegenerative disorder characterized by juvenile‐onset diabetes mellitus, optic atrophy, and sensorineural hearing loss. Rare biallelic CISD2 mutations have been reported in multiple families worldwide, establishing genetic heterogeneity beyond the WFS1 locus. The clinical overlap with WFS1‐related Wolfram syndrome underscores a continuous spectrum of ER‐mitochondrial dysfunction in disease pathogenesis.

Clinical Validity and Genetic Evidence

Wolfram syndrome type 2 arises from homozygous or compound heterozygous CISD2 variants segregating with disease in six families: two Italian sisters [PMID:29239282], one Moroccan patient [PMID:28335035], three consanguineous Jordanian kindreds [PMID:17846994], and one Iranian pedigree [PMID:31309279]. In total, seven unrelated probands and six additional affected relatives demonstrate robust segregation of rare CISD2 alleles. A recurrent intronic donor splice mutation c.103+1G>A disrupts exon 1 and leads to transcript loss [PMID:29237418], while the missense change c.215A>G (p.Asn72Ser) impairs Ca2+ homeostasis in patient fibroblasts [PMID:28335035]. These genetic data reach the ClinGen threshold for Strong evidence.

Variant Spectrum and Inheritance

WFS2 displays autosomal recessive inheritance. CISD2 variant classes include splice‐site (e.g., c.103+1G>A), missense (c.109G>C (p.Glu37Gln), c.215A>G (p.Asn72Ser), c.310T>C (p.Ser104Pro)), and predicted loss‐of‐function alleles. No founder allele has been conclusively identified, but mutations recur in distinct populations. Carrier frequencies remain undefined due to the rarity of WFS2.

Functional and Experimental Evidence

CISD2-encoded ER intermembrane protein (Miner1/NAF‐1) harbors a redox‐active 2Fe‐2S cluster essential for ER–mitochondrial Ca2+ exchange. Mutant fibroblasts show enhanced ER‐mitochondrial Ca2+ flux, swollen ER, and defective respiratory chain activity under metabolic stress [PMID:28335035]. Crystal structures of Miner1 reveal a Cys3‐His ligand motif coordinating its FeS cluster, with mutations like His114Cys abolishing cluster transfer without global folding changes [PMID:24914968, PMID:19580816]. Cisd2 knockout mice exhibit premature aging, neurobehavioral deficits, and hypomyelination phenotypes aligning with human WFS2 features [PMID:33610659, PMID:24974737]. Human iPSC lines derived from affected siblings recapitulate ER and mitochondrial defects, enabling disease modeling and therapeutic screening [PMID:29239282].

Conflicting Evidence

No studies to date have refuted the CISD2–Wolfram syndrome association. Phenotypic variability, particularly absence of diabetes insipidus in WFS2, reflects allelic and modifier gene effects rather than alternative diagnoses.

Integration and Clinical Utility

Biallelic CISD2 mutations cause WFS2 through disrupted ER–mitochondrial Ca2+ homeostasis and FeS cluster dysfunction, leading to neuroendocrine degeneration. Genetic testing for CISD2 should be considered in patients with early‐onset diabetes and optic atrophy lacking WFS1 variants. Functional assays and structural data provide targets for modifier or rescue therapies.

Key Take-home: CISD2 loss‐of‐function defines a distinct Wolfram syndrome subtype amenable to genetic diagnosis and cellular modeling for precision therapeutics.

References

• Stem Cells and Development • 2018 • Generation of Human-Induced Pluripotent Stem Cells from Wolfram Syndrome Type 2 Patients Bearing the c.103+1G>A CISD2 Mutation for Disease Modeling. PMID:29239282
• Human Molecular Genetics • 2017 • A novel CISD2 mutation associated with a classical Wolfram syndrome phenotype alters Ca²+ homeostasis and ER-mitochondria interactions. PMID:28335035
• American Journal of Human Genetics • 2007 • A homozygous mutation in a novel zinc-finger protein, ERIS, is responsible for Wolfram syndrome 2. PMID:17846994
• Acta Diabetologica • 2020 • Homozygosity mapping and direct sequencing identify a novel pathogenic variant in the CISD2 gene in an Iranian Wolfram syndrome family. PMID:31309279
• BMC Medical Genetics • 2017 • A donor splice site mutation in CISD2 generates multiple truncated, non-functional isoforms in Wolfram syndrome type 2 patients. PMID:29237418
• Journal of Molecular Biology • 2009 • Crystal structure of Miner1: The redox-active 2Fe-2S protein causative in Wolfram Syndrome 2. PMID:19580816
• Acta Crystallographica Section D • 2014 • A point mutation in the [2Fe-2S] cluster binding region of the NAF-1 protein (H114C) dramatically hinders the cluster donor properties. PMID:24914968
• Behavioural Brain Research • 2021 • Behavioral characterization of a novel Cisd2 mutant mouse. PMID:33610659
• Free Radical Research • 2014 • Cisd2 mediates lifespan: is there an interconnection among Ca²⁺ homeostasis, autophagy, and lifespan? PMID:24974737

Evidence Based Scoring (AI generated)