Homozygous variants of EDAR underlying hypohidrotic ectodermal dysplasia in three consanguineous families

被引:6
作者
Khan, Sher Alam [1 ]
Rukan, Ayesha [2 ]
Ullah, Asmat [3 ]
Bibi, Nousheen [4 ]
Humayun, Muhammad [1 ]
Ullah, Wasim [1 ]
Raza, Rubab [5 ]
Muhammad, Noor [1 ]
Ahmad, Wasim [5 ]
Khan, Saadullah [1 ]
Umm-E-Kalsoom [2 ]
机构
[1] Kohat Univ Sci & Technol, Dept Biotechnol & Genet Engn, Kohat, Khyber Pakhtunk, Pakistan
[2] Hazara Univ, Dept Biochem, Mansehra, Khyber Pakhtunk, Pakistan
[3] Shaheed Zulfiqar Ali Bhutto Med Univ, Dept Mol Biol, Islamabad, Pakistan
[4] Shaheed Benazir Bhutto Women Univ, Dept Bioinformat, Peshawar, Pakistan
[5] Quaid I Azam Univ, Dept Biochem, Islamabad, Pakistan
关键词
EDAR; homozygous variants; hypohidrotic ectodermal dysplasia; protein modelling; RNA analysis; MUTATION; GENE; WNT10A;
D O I
10.1684/ejd.2020.3844
中图分类号
R75 [皮肤病学与性病学];
学科分类号
100206 ;
摘要
Background Hypohidrotic ectodermal dysplasia (HED) is a congenital anomaly characterized by hypohydrosis, hypotrichosis and hypodontia. Mutations in at least four genes (EDAR, EDARADD, WNT10A, TRAF6) have been reported to cause both autosomal recessive and autosomal dominant forms of HED. Mutations in two other genes (EDA and IKBKG) have been reported to cause X-linked HED. Objectives To clinically characterize three consanguineous families (A-C) segregating with autosomal recessive HED and identify possible disease-causing variants of EDAR and EDARADD genes. Materials and Methods The genes, EDAR and EDARADD, were sequenced in Family A and C, and exome sequencing was performed in Family B. Additionally, in Family A and C, the effect of the identified variants was examined by analysis of EDAR mRNA, extracted from hair follicles from both affected and unaffected members. Results Sequence analysis revealed three possible disease-causing EDAR variants including a novel splice acceptor site variant (IVS3-1G > A) in Family A and two previously reported mutations (p.[Ala26Val], p.[Arg25*]) in the two other families. Previously, the nonsense variant p.(Arg25*) was reported only in the heterozygous state. Analysis of the RNA, extracted from hair follicles, revealed skipping of a downstream exon in EDAR and complete degradation of EDAR mRNA in affected members in family A and C, respectively. Computational modelling validated the pathogenic effect of the two variants identified in Family B and C. Conclusion The three variants reported here expand the spectrum of EDAR mutations associated with HED which may further facilitate genetic counselling of families segregating with similar disorders in the Pakistani population.
引用
收藏
页码:408 / 416
页数:9
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