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Autosomal recessive hypotrichosis with loose anagen hairs associated with TKFC mutations*

2021-05-01Artigo científico Acesso aberto
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datacite.subject.fosCiências Médicas::Outras Ciências Médicas
datacite.subject.sdg03:Saúde de Qualidade
datacite.subject.sdg11:Cidades e Comunidades Sustentáveis
dc.contributor.authorOnoufriadis, A.
dc.contributor.authorCabezas, A.
dc.contributor.authorNg, J. C. F.
dc.contributor.authorCanales, J.
dc.contributor.authorCostas, M. J.
dc.contributor.authorRibeiro, J. M.
dc.contributor.authorRodrigues, J. R.
dc.contributor.authorMcAleer, M. A.
dc.contributor.authorCastelo‐Soccio, L.
dc.contributor.authorSimpson, M. A.
dc.contributor.authorFraternali, F.
dc.contributor.authorIrvine, A. D.
dc.contributor.authorCameselle, J. C.
dc.contributor.authorMcGrath, J. A.
dc.date.accessioned2026-03-05T15:07:34Z
dc.date.available2026-03-05T15:07:34Z
dc.date.issued2021-05-01
dc.description.abstractBackground: Loose anagen hair is a rare form of impaired hair anchorage in which anagen hairs that lack inner and outer root sheaths can be gently and painlessly plucked from the scalp. This condition usually occurs in children and is often self-limiting. A genetic basis for the disorder has been suggested but not proven. A better understanding the aetiology of loose anagen hair may improve prevention and treatment strategies. Objectives: To identify a possible genetic basis of loose anagen hair using next-generation DNA sequencing and functional analysis of variants identified. Methods: In this case study, whole-exome sequencing analysis of a pedigree with one affected individual with features of loose anagen hair was performed. Results: The patient was found to be compound heterozygous for two single-nucleotide substitutions in TKFC resulting in the following missense mutations: c.574G> C (p.Gly192Arg) and c.682C> T (p.Arg228Trp). Structural analysis of human TKFC showed that both mutations are located near the active site cavity. Kinetic assays of recombinant proteins bearing either of these amino acid substitutions showed almost no dihydroxyacetone kinase or D-glyceraldehyde kinase activity, and FMN cyclase activity reduced to just 10% of wildtype catalytic activity. Conclusions: TKFC missense mutations may predispose to the development of loose anagen hairs. Identification of this new biochemical pathobiology expands the metabolic and genetic basis of hypotrichosis.eng
dc.description.sponsorshipFunding sources: This study was supported by the UK National Institute for Health Research comprehensive Biomedical Research Centre award to Guy’s and St. Thomas’ NHS Foundation Trust, in partnership with King’s College London and King’s College Hospital NHS Foundation Trust. This work was also funded by the National Children’s Research Centre, Dublin. J.C.F.N. is supported by a studentship from the Croucher Foundation, Hong Kong. L.C.S. is supported by a Career Development Award from the Dermatology Foundation. F.F. is supported by the Medical Research Council (MR/L01257X/1). The work in Leiria was financially supported by Associate Laboratory LSRE‐LCM ‐ UID/EQU/50020/2019, funded by national funds through FCT/MCTES (PIDDAC). Research in the Grupo de Enzimología in Badajoz is funded by Consejería de Economía e Infraestructuras, Junta de Extremadura, Spain (grant numbers IB16066 and GR18127), cofunded by the European Regional Development Fund. Acknowledgments We would like to thank the patient and her family members who kindly contributed samples and granted permission to publish this work. We acknowledge assistance with hair microscopy from Michael McDermott and from Dong Li for WES data mining.
dc.identifier.citationA. Onoufriadis, A. Cabezas, J.C.F. Ng, J. Canales, M.J. Costas, J.M. Ribeiro, J.R. Rodrigues, M.A. McAleer, L. Castelo‐Soccio, M.A. Simpson, F. Fraternali, A.D. Irvine, J.C. Cameselle, J.A. McGrath, Autosomal recessive hypotrichosis with loose anagen hairs associated with TKFC mutations, British Journal of Dermatology, Volume 184, Issue 5, 1 May 2021, Pages 935–943, https://doi.org/10.1111/bjd.19481.
dc.identifier.doi10.1111/bjd.19481
dc.identifier.eissn1365-2133
dc.identifier.issn0007-0963
dc.identifier.urihttp://hdl.handle.net/10400.8/15789
dc.language.isoeng
dc.peerreviewedyes
dc.publisherOxford University Press
dc.relationLaboratory of Separation and Reaction Engineering
dc.relation.hasversionhttps://academic.oup.com/bjd/article/184/5/935/6702300
dc.relation.ispartofBritish Journal of Dermatology
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectAlopecia
dc.subjectChild
dc.subjectHair
dc.subjectHair Diseases
dc.subjectHumans
dc.subjectHypotrichosis
dc.subjectMutation
dc.titleAutosomal recessive hypotrichosis with loose anagen hairs associated with TKFC mutations*eng
dc.typejournal article
dspace.entity.typePublication
oaire.awardNumberUID/EQU/50020/2019
oaire.awardTitleLaboratory of Separation and Reaction Engineering
oaire.awardURIhttp://hdl.handle.net/10400.8/14046
oaire.citation.endPage943
oaire.citation.issue5
oaire.citation.startPage935
oaire.citation.titleBritish Journal of Dermatology
oaire.citation.volume184
oaire.fundingStreamFinanciamento do Plano Estratégico de Unidades de I&D - 2019
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85
person.familyNameRodrigues
person.givenNameJoaquim Rui
person.identifier.ciencia-id9018-0B83-E2C6
person.identifier.orcid0000-0002-9756-1124
person.identifier.ridL-4137-2014
person.identifier.scopus-author-id10242931100
relation.isAuthorOfPublication52f6ffb2-43e9-4f78-b414-dbac46f80305
relation.isAuthorOfPublication.latestForDiscovery52f6ffb2-43e9-4f78-b414-dbac46f80305
relation.isProjectOfPublicationc13d02fe-f4a5-4340-ad91-5b29fd7ed567
relation.isProjectOfPublication.latestForDiscoveryc13d02fe-f4a5-4340-ad91-5b29fd7ed567

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Background: Loose anagen hair is a rare form of impaired hair anchorage in which anagen hairs that lack inner and outer root sheaths can be gently and painlessly plucked from the scalp. This condition usually occurs in children and is often self-limiting. A genetic basis for the disorder has been suggested but not proven. A better understanding the aetiology of loose anagen hair may improve prevention and treatment strategies. Objectives: To identify a possible genetic basis of loose anagen hair using next-generation DNA sequencing and functional analysis of variants identified. Methods: In this case study, whole-exome sequencing analysis of a pedigree with one affected individual with features of loose anagen hair was performed. Results: The patient was found to be compound heterozygous for two single-nucleotide substitutions in TKFC resulting in the following missense mutations: c.574G> C (p.Gly192Arg) and c.682C> T (p.Arg228Trp). Structural analysis of human TKFC showed that both mutations are located near the active site cavity. Kinetic assays of recombinant proteins bearing either of these amino acid substitutions showed almost no dihydroxyacetone kinase or D-glyceraldehyde kinase activity, and FMN cyclase activity reduced to just 10% of wildtype catalytic activity. Conclusions: TKFC missense mutations may predispose to the development of loose anagen hairs. Identification of this new biochemical pathobiology expands the metabolic and genetic basis of hypotrichosis.
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LSRE-LCM - Artigos em Revistas Nacionais e de Circulação Internacional
ESTG - Artigos em revistas internacionais