The human WS1 gene (WFS1) was identified in 1998
[14,15][14][15]. It is located on chromosome 4p16, consists of eight exons, and encodes wolframin, a transmembrane glycoprotein of 890 amino acids (aa) in the endoplasmic reticulum (ER). Wolframin consists of nine transmembrane segments and a large hydrophilic region at both ends
[16].
WFS1 is highly expressed in brain tissue, pancreatic β-cells, heart, lung, and placenta
[17]. Thus far, over 200 mutations have been found in the
WFS1 gene, and most of them are in exon 8 (
https://www.ncbi.nlm.nih.gov/clinvar/, accessed on 10 February 2022)
[18]. The region of exon 8 encodes the transmembrane and C-terminal domain of wolframin, which is important for the functionality of this protein
[14,19][14][19].
WFS1 mutations are frequently inactivating (nonsense or frameshift)
[18], and most of them are transmitted in an autosomal recessive mode. However, autosomal dominant mutations have been found in WS-like diseases, such as
WFS1-related non-syndromic low-frequency sensorineural hearing loss (LFSNHL)
[20,21][20][21]. Specifically,
WFS1 mutations have been also implicated in non-syndromic hearing loss DFNA6/14/38
[22]. The great number of
WFS1 mutations, the complexity of the clinical picture of WS1, and the small number of patients (30–60 patients) do not allow a genotype-phenotype correlation
[18]. De Heredia et al. analyzed both genetical and clinical data from 412 WS1 patients published since 1998 and found 178 mutations in
WFS1 [23]. The mutations were classified according to their effect on
WFS1 expression, and it was suggested that patients with mutations causing absent wolframin production were more likely to have earlier onset diabetes mellitus, and perhaps earlier onset of optic atrophy, than patients with residual wolframin expression. Rigoli et al. studied 44 WS1 patients of Italian ethnicity and 1 Arab male (Morocco).
In this stMu
dy, mutations were subdivided into three groups according to predicted functional consequences, as the high genetic heterogeneity of
WFS1 complicated genotype-phenotype correlations
[10]. WS1 patients with nonsense mutations and frameshift and/or multiple amino acid insertion/deletions in both alleles resulting in absence of wolframin were included in group 1. Group 2 consisted of WS1 patients with missense mutations and/or single amino acid insertions in both alleles. Most of
WFS1 variants included in group 2 result in milder degradation of wolframin than those in group 1. Compound heterozygous WS1 patients with mutations not found in groups 1 and 2 were included in group 3. It was found that the age of onset of DM, D, and DI but not of OA differed between the three groups. Furthermore, the survival time of patients in group 1 tended to be shorter than that of patients in the other groups. The type of clinical manifestations of the WS1 patients was not different among the 3 groups. The results of the study in Italian patients suggest that there may be a genotype-phenotype correlation in WS1. The genetic and clinical study of a larger number of WS1 patients could elucidate the pathogenetic mechanisms of WS1
[10].
A second rare and neurodegenerative type of WS has been described, namely WS2, which is transmitted in an autosomal recessive mode. WS2 is caused by mutations in CDGSH iron-sulfur domain-containing protein 2 (
CISD2) gene, which maps to chromosome 4q22-q23 and consists of three exons
[24].
CISD2 encodes the zinc-finger protein named “small intermembrane endoplasmic reticulum protein” (ERIS), which is highly expressed in tissues such as pancreas and brain
[25]. Although the function of ERIS is not fully known, it has been found that it transfers iron to the mitochondria and thus is important for the regulation of iron and reactive oxygen species (ROS). Furthermore, ERIS plays a central role in the regulation of mitochondrial homeostasis and exchanges between ER and mitochondria and in the activation of autophagy and apoptosis
[26]. The clinical features that characterize WS2 are still not completely established, as there are few affected subjects. The main symptoms of WS2 are ulcers of the upper intestine, mucocutaneous bleeding, and defective platelet aggregation, which are pathognomonic of WS2 and which are absent in WS1
[27,28][27][28]. They have been found in over 90% of patients affected by WS2. Therefore, they are useful clinical criteria for a differential diagnosis with WS1. Juvenile onset DM, variable degrees of OA, high-frequency sensorineural hearing impairment, DI, neurological and psychiatric abnormalities, endocrine disorders, and impaired renal function have also been reported. OA is progressive and is associated with loss of ganglion cells, but it is milder and less progressive than that of WS1. It has been suggested that optic nerve involvement is consistent with a diagnosis of optic neuropathy and not of optic atrophy
[28].