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Wolfram syndrome 1 (WS1) is a rare autosomal recessive neurodegenerative disorder characterized by juvenile-onset non-autoimmune diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing loss (DIDMOAD) ([PMID:24218323]). The syndrome typically presents in childhood, with insulin-dependent diabetes by age 6 and optic atrophy by age 11. WS1 results from biallelic pathogenic variants in WFS1, which encodes wolframin, an endoplasmic reticulum (ER) transmembrane glycoprotein crucial for ER Ca²⁺ homeostasis and the unfolded protein response ([PMID:12913071]; [PMID:15994758]). Wolframin is highly expressed in pancreatic β cells, retinal ganglion cells, and neurons, aligning with the clinical phenotype.
Autosomal recessive inheritance of WS1 is well-established, with at least 30 unrelated probands reported across multiple cohorts ([PMID:31850070]; [PMID:36098976]; [PMID:24218323]). Segregation analyses in consanguineous families demonstrate cosegregation of biallelic WFS1 variants in 7 additional affected relatives ([PMID:32938580]). Penetrance is high for the core features, with rare reports of incomplete phenotypes or late onset, underscoring genetic heterogeneity and modifier effects.
The WFS1 variant spectrum encompasses over 200 distinct alleles, including nonsense, frameshift, missense, splice-site, copy-number, and deep intronic variants. Loss-of-function alleles predominate, but missense substitutions in luminal and transmembrane domains are frequent. A representative in-frame deletion, c.1620_1622del (p.Trp540del), was identified in an atypical late-onset WS1 patient without diabetes insipidus ([PMID:35206658]). Recurrent alleles such as c.2020G>A (p.Gly674Arg) in Chinese cohorts further illustrate population-specific founder effects ([PMID:36098976]).
Functional studies confirm that pathogenic WFS1 variants lead to reduced wolframin stability and accelerated proteasomal degradation in patient-derived cells and heterologous systems ([PMID:16806192]). ER stress assays show upregulation of UPR markers including GRP78 and ATF6α upon expression of mutant alleles ([PMID:15994758]). ER Ca²⁺ imaging reveals impaired store-operated Ca²⁺ entry in WFS1 knockdown cells, implicating wolframin in ER Ca²⁺ filling ([PMID:16989814]). Wfs1-knockout mice replicate key WS1 features—β-cell loss, optic nerve degeneration, and neurological deficits—validating pathogenic mechanisms.
The pathogenic mechanism in WS1 is loss-of-function of wolframin leading to ER Ca²⁺ dyshomeostasis, chronic ER stress, and apoptosis in pancreatic β cells and neural tissues. Haploinsufficiency underlies the core phenotype, while modifier genes and environmental factors may influence expressivity. Concordance between human and animal model phenotypes strengthens causal inference.
In summary, strong genetic and experimental evidence establishes biallelic WFS1 variants as the cause of autosomal recessive WS1. Genetic testing of WFS1 enables definitive diagnosis, informs carrier screening, guides multidisciplinary management of endocrine and neurological complications, and supports reproductive counseling. Key take‐home: Early identification of WFS1 pathogenic variants is essential for timely intervention and improved clinical outcomes in Wolfram syndrome 1.
Gene–Disease AssociationStrong30 unrelated probands ([PMID:31850070]; [PMID:36098976]; [PMID:24218323]), segregation in 7 affected relatives ([PMID:32938580]), concordant functional data Genetic EvidenceStrongMultiple biallelic LoF and missense variants in >30 probands under AR inheritance; full genetic cap reached Functional EvidenceModerateCellular assays and knockout mice show ER stress‐mediated loss-of-function consistent with human phenotype |