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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

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Front. Med.    2022, Vol. 16 Issue (5) : 808-814    https://doi.org/10.1007/s11684-021-0878-x
LETTER TO FRONTIERS OF MEDICINE
Novel variants in LAMA3 and COL7A1 and recurrent variant in KRT5 underlying epidermolysis bullosa in five Chinese families
Rongrong Wang1, Liwei Sun1, Xiaerbati Habulieti1,2, Jiawei Liu3, Kexin Guo1, Xueting Yang1, Donglai Ma3(), Xue Zhang1()
1. McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing 100005, China
2. The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830001, China
3. Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing 100072, China
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Abstract

Epidermolysis bullosa (EB) is a group of clinically and genetically heterogeneous diseases characterized by trauma-induced mucocutaneous fragility and blister formation. Here, we investigated five Chinese families with EB, and eight variants including a novel nonsense variant (c.47G>A, p.W16*) in LAMA3, a known recurrent variant (c.74C>T, p.P25L) in KRT5, 2 novel (c.2531T>A, p.V844E; c.6811_6814del, p.R2271fs) and 4 known (c.6187C>T, p.R2063W; c.7097G>A, p.G2366D; c.8569G>T, p.E2857*; c.3625_3635del, p.S1209fs) variants in COL7A1 were detected. Notably, this study identified a nonsense variant in LAMA3 that causes EB within the Chinese population and revealed that this variant resulted in a reduction in LAMA3 mRNA and protein expression levels by nonsense-mediated mRNA decay. Our study expands the mutation spectra of Chinese patients with EB.
Keywords epidermolysis bullosa      LAMA3      COL7A1      KRT5      Chinese families     
Corresponding Author(s): Donglai Ma,Xue Zhang   
Just Accepted Date: 31 December 2021   Online First Date: 17 March 2022    Issue Date: 18 November 2022
 Cite this article:   
Rongrong Wang,Liwei Sun,Xiaerbati Habulieti, et al. Novel variants in LAMA3 and COL7A1 and recurrent variant in KRT5 underlying epidermolysis bullosa in five Chinese families[J]. Front. Med., 2022, 16(5): 808-814.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-021-0878-x
https://academic.hep.com.cn/fmd/EN/Y2022/V16/I5/808
Fig.1  Clinical features and molecular characterization of Family 1 with nonsense variant c.47G>A [p.W16*] in LAMA3. (A) Clinical manifestations of the affected proband (II-1) and proband’s brother (II-2) in Family 1. (a–c) Clinical manifestations of proband (II-1): (a) Severe fingernail onychodystrophy, (b) blisters and scars on extremities and elbows and hypertrophic scars in the armpit, and (c) severe enamel hypoplasia (discoloration, pitted teeth, and hypodontia), excessive carious lesions in oral cavity, and erosions in orofacial regions. (d–f) Clinical manifestations of proband’s brother (II-2): (d) Eyelid scarring and symblepharon in his eye margin, (e) scars on the extremities and neck, (f) severe scars widely distributed in his lower limb. (B) Molecular characterization of the nonsense variant c.47G>A [p.W16*] in LAMA3. (a) Pedigree with indicated genotypes of studied individuals (WT, wild type) in Family 1. Males, females, and affected individuals are represented by squares, circles, and shading, respectively, and arrow indicates the proband. Individuals who underwent genetic testing are marked with an asterisk (*). (b) Sequence chromatogram depicting the nonsense variant c.47G>A [p.W16*] of LAMA3 in the pedigree, including mother of the proband (I-2), proband (II-1), and brother of the proband (II-2). (c) Real-time quantitative PCR results showing that the LAMA3A mRNA levels of the proband (II-1) and brother of the proband (II-2) in Family 1 were reduced to 23% and 28%, respectively, compared with the normal control (NC) individual. Each bar represents the mean±standard deviation (n = 4). (d) Western blotting results revealing that the protein levels of LAMA3A transcript (170 kDa) in the proband (II-1) and brother of the proband (II-2) were reduced significantly compared with that of the normal control (NC) individual. β-actin (42 kDa) was used as a loading control. (C) Schematic of LAMA3 with identified variants to date. The nonsense variant c.47G>A [p.W16*] identified in our study was highlighted in red. (S, laminin N-terminal; E, laminin EGF-like.)
Fig.2  Clinical features and molecular characterization of the Families 2, 3, and 4 with compound variants in COL7A1. (A) Pedigree with indicated genotypes of studied individuals (WT, wild type) in Families 2, 3, and 4. Males, females, and affected individuals are represented by squares, circles, and shading, respectively, and arrow indicates the proband. Individuals who underwent genetic testing are marked with an asterisk (*). Sequence chromatogram depicting the compound variants of the c.6811_6814del [p.R2271fs] and c.2531T>A [p.V844E] of COL7A1 in Family 2, compound variants of the c.3625_3635del [p.S1209fs] and c.8569G>T [p.E2857*] of COL7A1 in Family 3, and compound variants of the c.6187C>T [p.R2063W] and c.7097G>A [p.G2366D] of COL7A1 in Family 4. (B) Clinical manifestations of affected probands of Families 2, 3, and 4: (a–c) Blistering on hands, elbows, and hemorrhagic blisters on neck of proband (II-1) in Family 2; (d–f) blistering, scarring, erythema, ulceration, and crust on hands, feet, and elbows of proband (II-1) of Family 3; and (g–k) severe hemorrhagic blisters in neck, blistering, and excoriated lesions on abdomen, hands, and feet of proband (II-1) in Family 4. (C) Overview of locations of variants identified in our study in the type VII collagen protein with the noncollagenous-1 (NC1), triple-helix (THD), and noncollagenous-2 domains (NC2).
Fig.3  Molecular characterization of Family 5 with missense variant in KRT5. (A) Pedigree with indicated genotypes of studied individuals (WT, wild type) in Family 5. Males, females, and affected individuals are represented by squares, circles, and shading, respectively, and arrow indicates the proband. Individuals who underwent genetic testing are marked with an asterisk (*). (B) Sequence chromatogram depicting the variant c.74C>T [p. P25L] in KRT5 in the proband (II-1) and mother (I-2) of the proband.
Family Phenotype Gene Inheritance
1 Scars on elbow and orofacial regions, dental enamel defects, nail defects, and hypertrophic scars in the armpit LAMA3 AR
2 Nail dystrophy and loss with granulation tissue of nail beds and scarring and blistering on hands, neck, back hands, and elbow regions COL7A1 AR
3 Blistering and excoriated lesions on her neck, abdomen, extremities and healed with hypertrophic scars; severe hemorrhagic blisters in neck; dysphagia; nail dystrophy; and partial nail loss COL7A1 AR
4 Scarring, erythema, ulceration, crust on his hands, feet, and elbows; blistering on the joint of hands and feet; esophageal strictures COL7A1 AR
AR
5 Blistering from birth especially on friction sites, additional mottled or reticulate macular pigmentation typically of the previous blistering skin KRT5 AD
Family Variant type Exon cDNA change Amino acid change Reference
1 Homozygous 1 c.47G>A p.W16* Present study
2 Heterozygous
Heterozygous		 86
19		 c.6811_6814del
c.2531T>A		 p.R2271fs
p.V844E		 Present study
Present study
3 Heterozygous
Heterozygous		 74
92		 c.6187C>T
c.7097G>A		 p.R2063W
p.G2366D		 [18,19]
[12]
4 Heterozygous
Heterozygous		 27
116		 c.3625_3635del
c. 8569G>T		 p.S1209fs
p.E2857*		 [20]
[21,22]
5 Homozygous 1 c.74C>T p.P25L [11–17]
Tab.1  Phenotype and molecular characterization of probands with epidermolysis bullosa from five Chinese families
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