Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis.

Pure hair and nail ectodermal dysplasia (PHNED) comprises a heterogeneous group of rare heritable disorders characterized by brittle hair, hypotrichosis, onychodystrophy and micronychia. Autosomal recessive (AR) PHNED has previously been associated with mutations in either KRT85 or HOXC13 on chromos...

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Autores principales:	Doroteya Raykova, Joakim Klar, Aysha Azhar, Tahir Naeem Khan, Naveed Altaf Malik, Muhammad Iqbal, Muhammad Tariq, Shahid Mahmood Baig, Niklas Dahl
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/be1adbe3ffec4a89b125b16f67381000
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spelling	oai:doaj.org-article:be1adbe3ffec4a89b125b16f673810002021-11-18T08:24:30ZAutosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis.1932-620310.1371/journal.pone.0093607https://doaj.org/article/be1adbe3ffec4a89b125b16f673810002014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24714551/?tool=EBIhttps://doaj.org/toc/1932-6203Pure hair and nail ectodermal dysplasia (PHNED) comprises a heterogeneous group of rare heritable disorders characterized by brittle hair, hypotrichosis, onychodystrophy and micronychia. Autosomal recessive (AR) PHNED has previously been associated with mutations in either KRT85 or HOXC13 on chromosome 12p11.1-q14.3. We investigated a consanguineous Pakistani family with AR PHNED linked to the keratin gene cluster on 12p11.1 but without detectable mutations in KRT85 and HOXC13. Whole exome sequencing of affected individuals revealed homozygosity for a rare c.821T>C variant (p.Phe274Ser) in the KRT74 gene that segregates AR PHNED in the family. The transition alters the highly conserved Phe274 residue in the coil 1B domain required for long-range dimerization of keratins, suggesting that the mutation compromises the stability of intermediate filaments. Immunohistochemical (IHC) analyses confirmed a strong keratin-74 expression in the nail matrix, the nail bed and the hyponychium of mouse distal digits, as well as in normal human hair follicles. Furthermore, hair follicles and epidermis of an affected family member stained negative for Keratin-74 suggesting a loss of function mechanism mediated by the Phe274Ser substitution. Our observations show for the first time that homozygosity for a KRT74 missense variant may be associated with AR PHNED. Heterozygous KRT74 mutations have previously been associated with autosomal dominant woolly hair/hypotrichosis simplex (ADWH). Thus, our findings expand the phenotypic spectrum associated with KRT74 mutations and imply that a subtype of AR PHNED is allelic with ADWH.Doroteya RaykovaJoakim KlarAysha AzharTahir Naeem KhanNaveed Altaf MalikMuhammad IqbalMuhammad TariqShahid Mahmood BaigNiklas DahlPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 4, p e93607 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Doroteya Raykova Joakim Klar Aysha Azhar Tahir Naeem Khan Naveed Altaf Malik Muhammad Iqbal Muhammad Tariq Shahid Mahmood Baig Niklas Dahl Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis.
description	Pure hair and nail ectodermal dysplasia (PHNED) comprises a heterogeneous group of rare heritable disorders characterized by brittle hair, hypotrichosis, onychodystrophy and micronychia. Autosomal recessive (AR) PHNED has previously been associated with mutations in either KRT85 or HOXC13 on chromosome 12p11.1-q14.3. We investigated a consanguineous Pakistani family with AR PHNED linked to the keratin gene cluster on 12p11.1 but without detectable mutations in KRT85 and HOXC13. Whole exome sequencing of affected individuals revealed homozygosity for a rare c.821T>C variant (p.Phe274Ser) in the KRT74 gene that segregates AR PHNED in the family. The transition alters the highly conserved Phe274 residue in the coil 1B domain required for long-range dimerization of keratins, suggesting that the mutation compromises the stability of intermediate filaments. Immunohistochemical (IHC) analyses confirmed a strong keratin-74 expression in the nail matrix, the nail bed and the hyponychium of mouse distal digits, as well as in normal human hair follicles. Furthermore, hair follicles and epidermis of an affected family member stained negative for Keratin-74 suggesting a loss of function mechanism mediated by the Phe274Ser substitution. Our observations show for the first time that homozygosity for a KRT74 missense variant may be associated with AR PHNED. Heterozygous KRT74 mutations have previously been associated with autosomal dominant woolly hair/hypotrichosis simplex (ADWH). Thus, our findings expand the phenotypic spectrum associated with KRT74 mutations and imply that a subtype of AR PHNED is allelic with ADWH.
format	article
author	Doroteya Raykova Joakim Klar Aysha Azhar Tahir Naeem Khan Naveed Altaf Malik Muhammad Iqbal Muhammad Tariq Shahid Mahmood Baig Niklas Dahl
author_facet	Doroteya Raykova Joakim Klar Aysha Azhar Tahir Naeem Khan Naveed Altaf Malik Muhammad Iqbal Muhammad Tariq Shahid Mahmood Baig Niklas Dahl
author_sort	Doroteya Raykova
title	Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis.
title_short	Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis.
title_full	Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis.
title_fullStr	Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis.
title_full_unstemmed	Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis.
title_sort	autosomal recessive transmission of a rare krt74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/be1adbe3ffec4a89b125b16f67381000
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Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis.

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