Loss-of-function variants in GLMN are associated with generalized skin hyperpigmentation with or without glomuvenous malformation
© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprintsoup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com..
BACKGROUNDS: Inherited hyperpigmented skin disorders comprise a group of entities with considerable clinical and genetic heterogenicity. The genetic basis of a majority of these disorders remains to be elucidated.
OBJECTIVES: This study aimed to identify the underlying gene for an unclarified disorder of autosomal-dominant generalized skin hyperpigmentation with or without glomuvenous malformation.
METHODS: Whole-exome sequencing was performed in five unrelated families with autosomal-dominant generalized skin hyperpigmentation. Variants were confirmed using Sanger sequencing and a minigene assay was employed to evaluate the splicing alteration. Immunofluorescence and transmission electron microscopy (TEM) were used to determine the quantity of melanocytes and melanosomes in hyperpigmented skin lesions. GLMN knockdown by siRNA assays was performed in human MNT-1 cells to examine melanin concentration and the underlying molecular mechanism.
RESULTS: We identified five variants in GLMN in five unrelated families, including c.995_996insAACA(p.Ser333Thrfs*11), c.632 + 4delA, c.1470_1473dup(p.Thr492fs*12), c.1319G > A(p.Trp440*), and c.1613_1614insTA(Thr540*). The minigene assay confirmed that the c.632 + 4delA mutant resulted in an abolishment of the canonical donor splice site. Although the number of melanocytes remained unchanged in skin lesions as demonstrated by immunofluorescent staining of tyrosinase and premelanosome protein (PMEL), TEM revealed an increased quantity of melanosomes in the skin lesion of a patient. The GLMN-knockdown MNT-1 cells demonstrated a higher melanin concentration, a higher proportion of stage III and IV melanosomes, upregulation of MITF and tyrosinase, and downregulation of phosphorylated p70S6 K, compared to mock-transfected cells.
CONCLUSIONS: We found loss-of-function variants in GLMN are associated with generalized skin hyperpigmentation with or without glomuvenous malformation. Our study implicates a potential role of glomulin in human skin melanogenesis, in addition to vascular morphogenesis.
| Errataetall: | |
|---|---|
| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
|---|---|
| Enthalten in: |
The British journal of dermatology - (2024) vom: 15. März |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Jiang, Xingyuan [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
|---|
| Anmerkungen: |
Date Revised 08.04.2024 published: Print-Electronic CommentIn: Br J Dermatol. 2024 Apr 08;:. - PMID 38584369 Citation Status Publisher |
|---|
| doi: |
10.1093/bjd/ljae108 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM369792661 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM369792661 | ||
| 003 | DE-627 | ||
| 005 | 20240408232714.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240316s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1093/bjd/ljae108 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1369.xml |
| 035 | |a (DE-627)NLM369792661 | ||
| 035 | |a (NLM)38489583 | ||
| 035 | |a (PII)ljae108 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Jiang, Xingyuan |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Loss-of-function variants in GLMN are associated with generalized skin hyperpigmentation with or without glomuvenous malformation |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 08.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: Br J Dermatol. 2024 Apr 08;:. - PMID 38584369 | ||
| 500 | |a Citation Status Publisher | ||
| 520 | |a © The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprintsoup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. | ||
| 520 | |a BACKGROUNDS: Inherited hyperpigmented skin disorders comprise a group of entities with considerable clinical and genetic heterogenicity. The genetic basis of a majority of these disorders remains to be elucidated | ||
| 520 | |a OBJECTIVES: This study aimed to identify the underlying gene for an unclarified disorder of autosomal-dominant generalized skin hyperpigmentation with or without glomuvenous malformation | ||
| 520 | |a METHODS: Whole-exome sequencing was performed in five unrelated families with autosomal-dominant generalized skin hyperpigmentation. Variants were confirmed using Sanger sequencing and a minigene assay was employed to evaluate the splicing alteration. Immunofluorescence and transmission electron microscopy (TEM) were used to determine the quantity of melanocytes and melanosomes in hyperpigmented skin lesions. GLMN knockdown by siRNA assays was performed in human MNT-1 cells to examine melanin concentration and the underlying molecular mechanism | ||
| 520 | |a RESULTS: We identified five variants in GLMN in five unrelated families, including c.995_996insAACA(p.Ser333Thrfs*11), c.632 + 4delA, c.1470_1473dup(p.Thr492fs*12), c.1319G > A(p.Trp440*), and c.1613_1614insTA(Thr540*). The minigene assay confirmed that the c.632 + 4delA mutant resulted in an abolishment of the canonical donor splice site. Although the number of melanocytes remained unchanged in skin lesions as demonstrated by immunofluorescent staining of tyrosinase and premelanosome protein (PMEL), TEM revealed an increased quantity of melanosomes in the skin lesion of a patient. The GLMN-knockdown MNT-1 cells demonstrated a higher melanin concentration, a higher proportion of stage III and IV melanosomes, upregulation of MITF and tyrosinase, and downregulation of phosphorylated p70S6 K, compared to mock-transfected cells | ||
| 520 | |a CONCLUSIONS: We found loss-of-function variants in GLMN are associated with generalized skin hyperpigmentation with or without glomuvenous malformation. Our study implicates a potential role of glomulin in human skin melanogenesis, in addition to vascular morphogenesis | ||
| 650 | 4 | |a Journal Article | |
| 700 | 1 | |a Yang, Chao |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Zhaoyang |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Lina |e verfasserin |4 aut | |
| 700 | 1 | |a Gong, Zhuoqing |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Shimiao |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Zigang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Bin |e verfasserin |4 aut | |
| 700 | 1 | |a Pei, Xiaoping |e verfasserin |4 aut | |
| 700 | 1 | |a Cai, Liangqi |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Huijun |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Zhimiao |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t The British journal of dermatology |d 1951 |g (2024) vom: 15. März |w (DE-627)NLM000000361 |x 1365-2133 |7 nnns |
| 773 | 1 | 8 | |g year:2024 |g day:15 |g month:03 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1093/bjd/ljae108 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |j 2024 |b 15 |c 03 | ||