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The N-terminal extracellular domain of the cadherins, calcium-dependent cell adhesion molecules, has been shown by x-ray crystallography to be involved in 2 types of interactions: lateral strand dimers and adhesive dimers. Rickman et al. (1999) described the first mutation in a cadherin present in desmosome cell junctions that removes a portion of this highly conserved first extracellular domain (125670.0001). This mutation, in the DSG1 gene coding for desmoglein-1, resulted in the deletion of the first and much of the second beta-strand of the first cadherin repeat and part of the first Ca(2+)-binding site, and would be expected to compromise strand dimer formation.


The heterozygous mutation identified by Rickman et al. (1999) (IVS3-1G-A; 125670.0001) occurred in a 3-generation Dutch family with striate palmoplantar keratoderma type I (PPKS1; 148700) and segregated with the disease. The mutation caused aberrant splicing of exon 2 to exon 4, which are in-frame, with the consequent removal of exon 3 encoding part of the prosequence, the mature protein cleavage site, and part of the first extracellular domain. This mutation emphasized the importance of this part of the molecule for cadherin function, and of the DSG1 protein and hence desmosomes in epidermal function. In the Dutch pedigree, affected individuals were present in 2 generations with male-to-male transmission. By inference, one member of an earlier generation was affected but was not clinically diagnosed. Rickman et al. (1999) concluded that haploinsufficiency was probably a mechanism of the dominant disorder in the family. The rather mild clinical symptoms could have been a consequence of the partial efficiency of missplicing and the fact that affected individuals were heterozygotes, so that only a fraction of DSG1 was of the abnormal type lacking exon 3.

Hunt et al. (2001) performed sequence analysis in 5 unrelated cases of keratosis palmoplantaris striata I and identified heterozygous mutations (in exons 2, 9, and 11) involving extracellular domains of the DSG1 protein (see, e.g., 125670.0002-125670.0004). All the mutations caused truncated proteins due to nonsense mutations or to deletions or insertions resulting in frameshifts, and haploinsufficiency was the most probable mechanism of the dominant inheritance of the disorder.

In a family of Jewish Yemenite origin with autosomal dominant diffuse PPK mapping to 18q12, Keren et al. (2005) analyzed the DSG1 gene and identified a heterozygous nonsense mutation (R26X; 125670.0004) that segregated completely with the disease. The same mutation had previously been detected in a sporadic patient with striate PPK (Hunt et al., 2001).

In a father and 2 daughters with a focal, nonstriated form of palmoplantar keratoderma from a consanguineous Libyan family, Milingou et al. (2006) identified heterozygosity for a frameshift mutation in the DSG1 gene (125670.0005) that was not found in unaffected family members or in 50 unrelated controls. The authors noted that the phenotype in this family extended the spectrum of clinical features associated with genetic defects in DSG1.

Hershkovitz et al. (2008) sequenced the DSG1 gene in 3 families with PPKS, including 1 of Jewish Sephardic descent and 2 of Jewish Ashkenazi origin, and identified 3 different heterozygous truncating mutations (see, e.g., 125670.0006) that segregated with disease in each family, respectively. Direct sequencing of cDNA derived from affected skin failed to reveal a pathogenic mutation, suggesting that PPKS results from haploinsufficiency for DSG1.

Dua-Awereh et al. (2009) sequenced the DSG1 gene in 5 Pakistani families segregating autosomal dominant PPKS and identified distinct heterozygous mutations in each family, including the recurrent R26X mutation (125670.0004). Consistent with previous reports, all 5 mutations were predicted to result in premature termination codons.

In affected members of 2 unrelated consanguineous families with congenital erythroderma with palmoplantar keratoderma, hypotrichosis, and hyper-IgE (EPKHE; 615508), Samuelov et al. (2013) identified 2 different homozygous mutations in the DSG1 gene (125670.0008 and 125670.0009). The mutations segregated with disease in each family, and all heterozygous carriers displayed palmoplantar hyperkeratotic papules and plaques, primarily in a nonstriated pattern. Functional analysis showed that both mutations resulted in loss of expression of DSG1 at the cell membrane.

Kiwamu Hatakeyama, Yoshikane Kikushige, Toshihiro Miyamoto, Koichi Akashi; Identification of Thrombospondin-1 As a Novel Substrate of Cereblon Responsible for IMiDs-Induced Venous Thromboembolism. Blood 2019; 134 (Supplement_1): 631. doi: -2019-125670 041b061a72


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