|Year : 2019 | Volume
| Issue : 4 | Page : 440
Novel mutations in SASH1 associated with dyschromatosis universalis hereditaria
Wei-Long Zhong1, Hui-Jun Wang2, Zhi-Miao Lin1, Yong Yang3
1 Department of Dermatology, Peking University First Hospital; Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China
2 Department of Dermatology, Peking University First Hospital; Beijing Key Laboratory of Molecular Diagnosis on Dermatoses; Peking-Tsinghua Center for Life Sciences; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
3 Department of Dermatology, Peking University First Hospital; Beijing Key Laboratory of Molecular Diagnosis on Dermatoses; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
|Date of Web Publication||7-Jun-2019|
Dr. Zhi-Miao Lin
Department of Dermatology, Peking University First Hospital, Beijing 100034
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Zhong WL, Wang HJ, Lin ZM, Yang Y. Novel mutations in SASH1 associated with dyschromatosis universalis hereditaria. Indian J Dermatol Venereol Leprol 2019;85:440
|How to cite this URL:|
Zhong WL, Wang HJ, Lin ZM, Yang Y. Novel mutations in SASH1 associated with dyschromatosis universalis hereditaria. Indian J Dermatol Venereol Leprol [serial online] 2019 [cited 2019 Jun 26];85:440. Available from: http://www.ijdvl.com/text.asp?2019/85/4/440/235388
Dyschromatosis universalis hereditaria is a group of congenital pigmentary disorders characterized by generalized mottled hypopigmented and hyperpigmented macules. It clinically overlaps with dyschromatosis symmetrica hereditaria and Dowling–Degos disease and genetically shows heterogeneity with at least two causative genes reported, viz., ABCB6 and SASH1., Here, we present two Chinese families with dyschromatosis universalis hereditaria and report two novel missense mutationsin SASH1 gene.
Two Chinese families with autosomal-dominant dyschromatosis universalis hereditaria were referred to our outpatient clinics [Figure 1]a and [Figure 1]b. Proband 1 was a 25-year-old woman born with normal skin pigmentation. At the age of 3 years, freckle-like macules appeared initially on her trunk, and then gradually extended to involve her face, neck and limbs with accentuation on sun-exposure areas. Hypopigmented patches were also noted on these areas intermingled with hyperpigmentation [Figure 1]c and [Figure 1]d. She was otherwise healthy. Her mother and deceased maternal grandfather had similar phenotypes. Proband 2 was a 42-year-old man who experienced a similar clinical process to that of the proband 1 but with an earlier onset at 7 months after birth. The dyschromatosis gradually progressed with age and involved nearly the whole body at the age of 7 years with sparing of the palmoplantar and mucosal areas [Figure 1]e, [Figure 1]f, [Figure 1]g. Affected family members showed similar clinical manifestations and were otherwise healthy.
Following informed consent and approval from Clinical Research Ethics Committee of Peking UniversityFirst Hospital, genomic DNA from the two probands were screened for mutations in the coding exons and their flanking sequences of ADAR, ABCB6 and SASH1 genes. As a result, two novel heterozygous missense mutations, c.1784T>C (p.M595T) and c.1651T>C (p.Y551H) [Figure 2]a and [Figure 2]b, in SASH1 were identified in probands 1 and 2, respectively. All living family members were genetically tested. The mutations segregated with the phenotype of dyschromatosis universalis hereditaria perfectly in both families. Both mutations were predicted to be “disease causing” (with a probability score of 0.999) in mutation taster (http://www.mutationtaster.org/). While M595T substitution was predicted to be “tolerated” with a score of 0.45 in SIFT (http://sift.bii.a-star.edu.sg) and “possibly damaging” with a score of 0.568 in polyphen2 (http://genetics.bwh.harvard.edu/pph2), the Y551H substitution was predicted to “affect protein function” with a score of 0.00 in SIFT and “probably damaging” with a score of 0.999 in polyphen2. Both mutated amino acids were highly conserved across different species.
SASH1 is located on chromosome 6q24.3, and encodes a signal adaptor protein (SASH1) of 1247 amino acids that contains an evolutionarily conserved SLY domain (401-555), an SH3 domain (557-614) and two SAM domains (633-697; 1177-1241, annotation from the UniProt database) [Figure 2]c. As a potential tumor suppressor, SASH1 gene has been reported to be involved in the tumorigenesis of lung cancer, breast cancer, colon cancer and melanoma. In addition, SASH1 has also been demonstrated to mediate skin melanogenesis through a cascade of p53/α-MSH/POMC/Gαs/SASH1. As shown in [Table 1], both autosomal-recessive and -dominant mutations in SASH1 have been associated with human skin dyschromia, including dyschromatosis universalis hereditaria, multiple lentigines and pigmentation defects with palmoplantar keratoderma and skin carcinoma., To date, seven of the eight different SASH1 mutations identified that result in skin dyschromia are located in the highly conserved SLY domain [Figure 2]c, suggesting that the SLY domain is functionally critical for skin pigmentation regulation and may represent a potential mutational hotspot region.,
|Table 1: Pigmentary genodermatosis and their clinical features with implicated SASH1 mutations|
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Mutation p.Y551H, which is located in the SLY domain, resulted in more generalized skin lesions and an earlier onset in proband 2, compared with proband 1. An alternative residue substitution in Y551 (p.Y551D) has been reported to result in dyschromatosis universalis hereditaria in another Chinese family. These data further confirm that the SLY domain is critical for mediation of melanogenesis and suggest that Y551 may be a mutation hotspot for dyschromatosis universalis hereditaria [Figure 2]c., The p.M595T is the first heterozygous missense mutation reported in the SH3 domain. SH3 domain can bind to proline-rich protein motifs and thus is critical for protein–protein interaction. It also mediates the formation of signaling complexes. We infer that mutation p.M595T may impede SASH1 interaction with other proteins and subsequent formation of signaling complexes. However, further functional studies are required to elucidate how this mutation affects the function of SASH1.
We thank all the patients and their family members for participating in this study. This work was supported by National Natural Science Foundation of China (grant no. 81573032), China National Funds for Excellent Young Scientists (grant no. 81522037) and Beijing Nova Program (grant no. Z151100000315044).
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their name and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
This work was supported by National Natural Science Foundation of China (grant no. 81573032), China National Funds for Excellent Young Scientists (grant no. 81522037) and Beijing Nova Program (grant no. Z151100000315044).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]