HGNC Approved Gene Symbol: DSG4
Cytogenetic location: 18q12.1 Genomic coordinates (GRCh38): 18:31,376,777-31,414,909 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q12.1 | Hypotrichosis 6 | 607903 | Autosomal recessive | 3 |
Desmoglein-4 is the principal desmosomal cadherin in the hair follicle, where it is a key mediator of keratinocyte cell adhesion and coordinates the transition from proliferation to differentiation (summary by Rafiq et al., 2004 and Schaffer et al., 2006).
Desmosomes are essential adhesion structures in most epithelia that link the intermediate filament network of one cell to its neighbor, thereby forming a strong bond. The molecular components of desmosomes belong to the cadherin superfamily (see 114020), the plakin family (see 125647), and the armadillo repeat protein family (see 602269). The desmosomal cadherins are calcium-dependent transmembrane adhesion molecules and comprise the desmogleins (see DSG1, 125670) and desmocollins (see 125643) (summary by Whittock and Bower, 2003).
Whittock and Bower (2003) identified and characterized, at the genetic level, a novel human desmoglein cDNA sharing homology with desmoglein-1 (DSG1), -2 (DSG2; 125671), and -3 (DSG3; 169615) and named it desmoglein-4 (DSG4). The 3.6-kb human DSG4 cDNA contains an open reading frame of 3,120 bp that encodes a precursor protein of 1,040 amino acids. The predicted mature protein comprises 991 amino acids with a molecular mass of 107,822 Da at pI 4.38. The human DSG4 protein shares 41%, 37%, and 50% sequence identity with human DSG1, DSG2, and DSG3, respectively. Using RT-PCR on multiple tissue cDNA samples, Whittock and Bower (2003) demonstrated that DSG4 has very specific tissue expression in salivary gland, testis, prostate, and skin.
By searching for homologs of mouse Dsg4 within the human desmoglein gene cluster, Kljuic et al. (2003) identified DSG4. The predicted mouse and human DSG4 proteins share 79% amino acid identity. Northern blot analysis detected a 5-kb DSG4 transcript in all mouse and human tissues tested, with high expression in skin. Immunofluorescence staining of human scalp sections localized DSG4 to the suprabasal epidermis. In situ hybridization revealed expression of Dsg4 in the mouse hair follicle.
Whittock and Bower (2003) demonstrated that the human DSG4 gene is composed of 16 exons spanning approximately 37 kb of genomic DNA and is situated between DSG1 and DSG3.
The DSG4 gene is situated within the desmoglein gene complex on chromosome 18q12 (Whittock and Bower, 2003).
Kljuic et al. (2003) showed that DSG4 is an autoantigen in pemphigus vulgaris (169610). Characterization of the phenotype of naturally occurring mutant mice revealed disruption of desmosomal adhesion and perturbations in keratinocyte behavior. Kljuic et al. (2003) provided evidence that DSG4 is a key mediator of keratinocyte cell adhesion in the hair follicle, where it coordinates the transition from proliferation to differentiation.
Using sera from patients with pemphigus and staphylococcal scalded skin syndrome (SSSS), Nagasaka et al. (2004) found that pemphigus sera showed DSG4 reactivity due to crossreactivity of a subset of anti-DSG1 IgG. There were no IgG autoantibodies that exclusively reacted with DSG4, and the DSG4/DSG1-crossreacting IgG had no demonstrable pathogenic effect. DSG4 was not cleaved by exfoliative toxins that induce blisters in SSSS. Nagasaka et al. (2004) suggested that DSG4 may play a role other than adhesion and that the crossreactivity of desmoglein autoantibodies should be taken into account in future studies of autoimmune mechanisms in pemphigus.
Kljuic et al. (2003) identified an identical homozygous 5-kb deletion within the DSG4 gene (607892.0001) in affected individuals from 2 consanguineous Pakistani families with localized autosomal recessive hypotrichosis (LAH1; 607903).
In 6 affected members of a large consanguineous Pakistani family with hypotrichosis, Wajid et al. (2007) identified homozygosity for a 1-bp deletion in the DSG4 gene (607892.0002).
In a Japanese girl with monilethrix-like congenital hypotrichosis (see 607903), who was negative for mutation in the 3 keratin genes known to cause monilethrix (158000), Shimomura et al. (2006) identified compound heterozygosity for a missense mutation and a 1-bp insertion in the DSG4 gene (607892.0003 and 607892.0004, respectively).
In 3 sibs of Iraqi and Iranian Jewish descent with monilethrix-like congenital hypotrichosis, Schaffer et al. (2006) identified compound heterozygosity for a splice site and a missense mutation in the DSG4 gene (607892.0005 and 607892.0006, respectively).
In 7 Iraqi Jewish patients with monilethrix-like congenital hypotrichosis mapping to a gene cluster on chromosome 18q, Zlotogorski et al. (2006) sequenced the candidate gene DSG4 and identified homozygosity for a missense mutation (607892.0006). Subsequently, compound heterozygosity for 3 additional mutations were detected, including a splice site mutation and a 1-bp deletion in patients of Iranian descent (607892.0005 and 607892.0007, respectively) and a nonsense mutation in patients of Moroccan descent (607892.0008).
In a 2-year-old Chinese girl with monilethrix-like congenital hypotrichosis, Wang et al. (2015) sequenced the DSG4 gene and identified homozygosity for a missense mutation (D323G; 607892.0009) that segregated with disease in the family and was not found in 100 unrelated controls or in public variant databases. The authors stated that this was the first reported Chinese patient with localized hypotrichosis.
In 2 apparently unrelated Muslim-Arab children with localized congenital hypotrichosis and follicular keratotic papules, Cohen-Barak et al. (2018) identified homozygosity for the same 4-bp deletion (607892.0010) in the DSG4 gene (607892.0010). The deletion, which was verified by Sanger sequencing and segregated with the phenotype in both families, was not found in 107 ethnicity-matched DNA samples or in the ExAC or gnomAD databases.
Kljuic et al. (2003) determined that mutations in the Dsg4 gene cause the lanceolate hair (lah) phenotype in mice, which maps to chromosome 18. Lah/lah pups develop only a few short, fragile hairs on the head and neck that disappear within a few months. The vibrissae are short and abnormal, and the pups have thickened skin. Mutant lah/lah mice do not exhibit any growth retardation relative to their unaffected littermates. A second allele of lah, designated lahJ, arose as a spontaneous mutation at the Jackson Laboratory. The lahJ/lahJ phenotype is more severe, as the pups fail to grow any normal hairs and completely lack vibrissae. Instead, lahJ/lahJ pups are covered with abnormally keratinized stubble, giving the mouse a 'peach fuzz' appearance. Sequence analysis of the Dsg4 gene in lahJ/lahJ mice revealed a homozygous 1-bp insertion (T) following nucleotide 746 within exon 7. Sequence analysis of the Dsg4 gene in lah/lah mice identified a homozygous A-to-C transversion at nucleotide 587 in exon 6, resulting in a tyr196-to-ser (Y196S) substitution.
Jahoda et al. (2004) discovered a missense mutation in the rat Dsg4 gene in a naturally occurring lah rat mutant with a striking hair shaft defect. The mutation resulted in a glu228-to-val (E228V) substitution. This glutamic acid is conserved in human, mouse, canine, and bovine desmogleins. It is part of a critical calcium-binding site bridging the second and third extracellular domains of Dsg4 required for adhesion between adjacent cells.
Kiener et al. (2022) studied 2 unrelated domestic shorthair cats with hair shaft dystrophy and mutations in the Dsg4 gene. Case 1 was a female that showed generalized hypotrichosis at 3 months of age, with symmetric hair loss affected the convex pinnae and parts of the face, back, and legs, including the dorsal paws. The cat was mildly pruritic. The trichogram showed broken and split hair shafts, with severe bulbous swellings. Case 2 was a male that previously had been studied by Rostaher et al. (2021) and exhibited progressive alopecia of the back, the plantar and palmar surfaces of the limbs, the convex pinnae, and most of the face. All of the cat's littermates showed similar skin lesions. Macroscopic and microscopic evaluation revealed many short broken hair shafts, some with bulbous or lance-shaped ends. Histopathology showed that numerous hair shafts were dystrophic, with severe well-circumscribed thickening of the shafts starting above the melanogenic zone. There was loss of the ladder-like pattern of pigment distribution. The dystrophy was characterized by an irregular outer contour of the hair shaft, fragmentation within the cortex and cuticle, and dense eosinophilic cornified material surrounding the hair shaft. The authors noted that the phenotype resembled that of Dsg4-null mice. Genomic analysis in both cats revealed different 1-bp deletions in the Dsg4 gene, causing frameshifts predicted to result in premature termination codons, truncating 98% and 43% of the open reading frame, respectively. The mutations were confirmed by Sanger sequencing and were not found in 46 unaffected cats.
In affected individuals from 2 consanguineous Pakistani pedigrees with localized autosomal recessive hypotrichosis (HYPT6; 607903), Kljuic et al. (2003) identified an identical homozygous deletion within the DSG4 gene. The deletion began 35 bp upstream of exon 5 and ended 289 bp downstream of exon 8. This mutation generated an in-frame deletion resulting in a predicted protein missing amino acids 125 to 335.
Rafiq et al. (2004) identified this deletion in 3 Pakistani families.
In 6 affected members of a large consanguineous Pakistani family with hypotrichosis (HYPT6; 607903), Wajid et al. (2007) identified homozygosity for a 1-bp deletion (87delG) in exon 3 of the DSG4 gene, causing a frameshift and a premature termination codon 162 bp downstream. The resulting mRNA transcript was predicted to be degraded by nonsense-mediated mRNA decay. Heterozygous carriers in the family were unaffected. The severity of hypotrichosis varied markedly among the affected family members, and hair shaft analysis showed monilethrix-like nodes.
In a Japanese girl with monilethrix-like congenital hypotrichosis (HYPT6; 607903), Shimomura et al. (2006) identified compound heterozygosity for a 574T-C transition in exon 6 of the DSG4 gene, resulting in a ser192-to-pro (S192P) substitution at a highly conserved residue within the second extracellular cadherin repeat (EC2), and a 1-bp insertion (2039_2040insT; 607892.0004) in exon 13, causing a frameshift and a premature termination codon just downstream of the insertion. Her unaffected mother was heterozygous for the missense mutation, whereas her unaffected father was heterozygous for the insertion. Neither mutation was found in 100 controls.
For discussion of the 1-bp insertion in the DSG4 gene (2039_2940insT) that was found in compound heterozygous state in a patient with monilethrix-like congenital hypotrichosis (HYPT6; 607903) by Shimomura et al. (2006), see 607892.0003.
In 3 sibs of Iraqi and Iranian Jewish descent with monilethrix-like congenital hypotrichosis (HYPT6; 607903), Schaffer et al. (2006) identified compound heterozygosity for a 216+1G-T transversion in the 5-prime donor splice site in intron 3 of the DSG4 gene, changing the invariant GT dinucleotide to TT and predicted to severely disrupt splice site recognition, and a missense mutation (P267R; 607892.0006). The unaffected parents were each heterozygous for 1 of the mutations, which were not found in 42 unrelated control individuals.
In affected individuals from 2 Jewish families of Iraqi and Iranian descent with monilethrix-like congenital hypotrichosis, Zlotogorski et al. (2006) identified compound heterozygosity for the 216+1G-T and the P267R mutations in the DSG4 gene. In a similarly affected brother and sister from an Iranian Jewish family, they identified compound heterozygosity for 216+1G-T and a 1-bp deletion in DSG4 (607892.0007). The splice site mutation was not found in 100 Iranian controls.
In 3 sibs of Iraqi and Iranian Jewish descent with monilethrix-like congenital hypotrichosis (HYPT6; 607903), Schaffer et al. (2006) identified compound heterozygosity for a missense mutation and a splice site mutation (607892.0005). The paternal allele carried an 800C-G transversion in exon 7 of the DSG4 gene, resulting in a pro267-to-arg (P267R) substitution at a highly conserved residue located at a critical position relative to the conserved calcium-binding pocket within the extracellular cadherin EC2-EC3 domain interface of DSG4. The unaffected parents were each heterozygous for 1 of the mutations, which were not found in 42 unrelated control individuals.
In affected individuals from 6 Iraqi Jewish families with monilethrix-like congenital hypotrichosis, Zlotogorski et al. (2006) identified homozygosity for the P267R mutation in the DSG4 gene. In similarly affected individuals from 2 families of Iraqi and Iranian Jewish descent, they identified compound heterozygosity for P276R and a splice site mutation in DSG4 (607892.0005), and in affected individuals from 2 families of Iraqi and Moroccan Jewish descent, they identified compound heterozygosity for P276R and a nonsense mutation in DSG4 (607892.0008). The P267R mutation was detected in 4 of 100 Iraqi Jewish controls, establishing a carrier rate of 1:25 in that population, but was not found in 100 controls from other ethnic groups.
In a brother and sister with monilethrix-like hypotrichosis (HYPT6; 607903) from an Iranian Jewish family, Zlotogorski et al. (2006) identified compound heterozygosity for a 1-bp del (763delT) and a splice site mutation (607892.0005) in the DSG4 gene. The 763delT mutation was found in 1 of 100 Iranian Jewish controls, establishing a carrier rate of 1:100 in that population.
In affected individuals from 2 Jewish families of Iraqi and Moroccan descent with monilethrix-like hypotrichosis (HYPT6; 607903), Zlotogorski et al. (2006) identified compound heterozygosity for an arg289-to-ter (R289X) substitution and the P267R missense mutation (607892.0006) in the DSG4 gene. The R289X mutation was found in 1 of 100 Moroccan Jewish controls, establishing a carrier rate of 1:100 in that population.
In a 2-year-old Chinese girl with monilethrix-like congenital hypotrichosis (HYPT6; 607903), Wang et al. (2015) identified homozygosity for a c.1103A-G transition in exon 8 of the DSG4 gene, resulting in an asp323-to-gly (D323G) substitution at a highly conserved residue. Her unaffected mother was heterozygous for the mutation, and 2 unaffected sibs did not carry the variant; DNA was unavailable from the proband's father. The mutation was not found in 100 unrelated controls, or in public variant databases.
In 2 apparently unrelated Muslim-Arab children with localized congenital hypotrichosis and follicular keratotic papules (HYPT6; 607903), Cohen-Barak et al. (2018) identified homozygosity for the same 4-bp deletion (c.126_129delAACA) in the DSG4 gene, causing a frameshift predicted to result in a premature termination codon (Thr43fsTer40). The deletion, which was verified by Sanger sequencing and segregated with the phenotype in both families, was not found in 107 ethnicity-matched DNA samples or in the ExAC or gnomAD databases. The authors suggested that the phenotype in the 2 children represented DSG4-associated keratosis pilaris atrophicans (see KPA, 604093).
Cohen-Barak, E., Danial-Farran, N., Hammad, H., Aleme, O., Krauz, J., Gavish, E., Khayat, M., Ziv, M., Shalev, S. Desmoglein 4 mutation underlies autosomal recessive keratosis pilaris atrophicans. Acta Derm. Venereol. 98: 809-810, 2018. [PubMed: 29796690] [Full Text: https://doi.org/10.2340/00015555-2976]
Jahoda, C. A. B., Kljuic, A., O'Shaughnessy, R., Crossley, N., Whitehouse, C. J., Robinson, M., Reynolds, A. J., Demarchez, M., Porter, R. M., Shapiro, L., Christiano, A. M. The lanceolate hair rat phenotype results from a missense mutation in calcium coordinating site of the desmoglein 4 gene. Genomics 83: 747-756, 2004. [PubMed: 15081105] [Full Text: https://doi.org/10.1016/j.ygeno.2003.11.015]
Kiener, S., Rostaher, A., Rufenacht, S., Jagannathan, V., Sundberg, J. P., Welle, M., Leeb, T. Independent DSG4 frameshift variants in cats with hair shaft dystrophy. Molec. Genet. Genomics 297: 147-154, 2022. [PubMed: 34878611] [Full Text: https://doi.org/10.1007/s00438-021-01842-6]
Kljuic, A., Bazzi, H., Sundberg, J. P., Martinez-Mir, A., O'Shaughnessy, R., Mahoney, M. G., Levy, M., Montagutelli, X., Ahmad, W., Aita, V. M., Gordon, D., Uitto, J., and 9 others. Desmoglein 4 in hair follicle differentiation and epidermal adhesion: evidence from inherited hypotrichosis and acquired pemphigus vulgaris. Cell 113: 249-260, 2003. [PubMed: 12705872] [Full Text: https://doi.org/10.1016/s0092-8674(03)00273-3]
Nagasaka, T., Nishifuji, K., Ota, T., Whittock, N. V., Amagai, M. Defining the pathogenic involvement of desmoglein 4 in pemphigus and staphylococcal scalded skin syndrome. J. Clin. Invest. 114: 1484-1492, 2004. [PubMed: 15545999] [Full Text: https://doi.org/10.1172/JCI20480]
Rafiq, M. A., Ansar, M., Mahmood, S., Haque, S., Faiyaz-ul-Haque, M., Leal, S. M., Ahmad, W. A recurrent intragenic deletion mutation in DSG4 gene in three Pakistani families with autosomal recessive hypotrichosis. J. Invest. Derm. 123: 247-248, 2004. [PubMed: 15191570] [Full Text: https://doi.org/10.1111/j.0022-202X.2004.22715.x]
Rostaher, A., Bettenay, S., Specht, L., Silva, K. A., Bechtold, L., Chen, J., Majzoub, M., Mueller, R. S., Sundberg, J. P. Hair follicle dystrophy in a litter of domestic cats resembling lanceolate hair mutant mice. Vet. Derm. 32: 74-e14, 2021. [PubMed: 33470013] [Full Text: https://doi.org/10.1111/vde.12925]
Schaffer, J. V., Bazzi, H., Vitebsky, A., Witkiewicz, A., Kovich, O. I., Kamino, H., Shapiro, L. S., Amin, S. P., Orlow, S. J., Christiano, A. M. Mutations in the desmoglein 4 gene underlie localized autosomal recessive hypotrichosis with monilethrix hairs and congenital scalp erosions. J. Invest. Derm. 126: 1286-1291, 2006. [PubMed: 16543896] [Full Text: https://doi.org/10.1038/sj.jid.5700237]
Shimomura, Y., Sakamoto, F., Kariya, N., Matsunaga, K., Ito, M. Mutations in the desmoglein 4 gene are associated with monilethrix-like congenital hypotrichosis. J. Invest. Derm. 126: 1281-1285, 2006. [PubMed: 16439973] [Full Text: https://doi.org/10.1038/sj.jid.5700113]
Wajid, M., Bazzi, H., Rockey, J., Lubetkin, J., Zlotogorski, A., Christiano, A. M. Localized autosomal recessive hypotrichosis due to a frameshift mutation in the desmoglein 4 gene exhibits extensive phenotypic variability within a Pakistani family. J. Invest. Derm. 127: 1779-1782, 2007. [PubMed: 17392831] [Full Text: https://doi.org/10.1038/sj.jid.5700791]
Wang, J.-M., Xiao, Y.-J., Liang, Y.-H. Novel D323G mutation of DSG4 gene in a girl with localized autosomal recessive hypotrichosis clinically overlapped with monilethrix. Int. J. Derm. 54: 1163-1168, 2015. [PubMed: 26173648] [Full Text: https://doi.org/10.1111/ijd.12889]
Whittock, N. V., Bower, C. Genetic evidence for a novel human desmosomal cadherin, desmoglein 4. J. Invest. Derm. 120: 523-530, 2003. [PubMed: 12648213] [Full Text: https://doi.org/10.1046/j.1523-1747.2003.12113.x]
Zlotogorski, A., Marek, D., Horev, L., Abu, A., Ben-Amitai, D., Gerad, L., Ingber, A., Frydman, M., Reznik-Wolf, H., Vardy, D. A., Pras, E. An autosomal recessive form of monilethrix is caused by mutations in DSG4: clinical overlap with localized autosomal recessive hypotrichosis. J. Invest. Derm. 126: 1292-1296, 2006. [PubMed: 16575393] [Full Text: https://doi.org/10.1038/sj.jid.5700251]