Autosomal Recessive Hypotrichosis with Woolly Hair Caused by a Mutation in the Keratin 25 Gene Expressed in Hair Follicles Nikolay V. Zernov, Mikhail.

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Autosomal Recessive Hypotrichosis with Woolly Hair Caused by a Mutation in the Keratin 25 Gene Expressed in Hair Follicles Nikolay V. Zernov, Mikhail Y. Skoblov, Andrey V. Marakhonov, Yutaka Shimomura, Tatyana A. Vasilyeva, Fedor A. Konovalov, Anna V. Abrukova, Rena A. Zinchenko Journal of Investigative Dermatology Volume 136, Issue 6, Pages 1097-1105 (June 2016) DOI: 10.1016/j.jid.2016.01.037 Copyright © 2016 The Authors Terms and Conditions

Figure 1 Phenotypic features of individuals from the first group affected by hypotrichosis 7. (a, b) Two affected individuals demonstrating low hair density varying from (a) hypotrichosis to (b) alopecia. (a) Short, sparse, deformed hair, highly placed frontotemporal hairline. (c, d) Hair light microscopy (LM). (c) LM showing thin hair (approximately 25 μm in diameter), high differences in diameters, and local variations in diameter of hair shaft (HS), (d) trichoptilosis. Scale bar = 100 μM. Written permission to publish photographs was obtained from all study participants. Journal of Investigative Dermatology 2016 136, 1097-1105DOI: (10.1016/j.jid.2016.01.037) Copyright © 2016 The Authors Terms and Conditions

Figure 2 A familial case #002 with autosomal recessive hypotrichosis with woolly hair. (a, c) Phenotypes of unaffected heterozygous parents and (b, d) light microscopy (LM) of their scalp hairs. (e, f, h, i) Phenotypes of the sisters affected by autosomal recessive hypotrichosis with woolly hair. Both show similar features: thin and curled scalp hair, decreased density from the occipital to the temporal region; frontotemporal hairline is close to normal. (g, j) LM of their scalp hairs showing thin hair (approximately 60 μm), slight differences in hair diameters, irregular wavy hair shaft contours. Scale bar = 100 μM. Written permission to publish photographs was obtained from all study participants. Journal of Investigative Dermatology 2016 136, 1097-1105DOI: (10.1016/j.jid.2016.01.037) Copyright © 2016 The Authors Terms and Conditions

Figure 3 Affected individual from nonfamilial case #041 with autosomal recessive hypotrichosis with woolly hair. (a, b) Phenotype features: tightly curled and thin scalp hair, decreased density from the occipital to the temporal region; frontotemporal hairline is close to normal. (c) Light microscopy (LM) showing trichorrhexis nodosa. Scale bar = 100 μM. Written permission to publish photographs was obtained from all study participants. Journal of Investigative Dermatology 2016 136, 1097-1105DOI: (10.1016/j.jid.2016.01.037) Copyright © 2016 The Authors Terms and Conditions

Figure 4 Identification of a mutation c.712G>T in type I cytoskeletal keratin 25 (KRT25) gene. Position g.chr17:38907536 (hg19) is marked in blue and indicated by an arrow. (a) Healthy control individual. (b, c) Healthy heterozygous parents and two (d, e) affected girls from familial case #002. (f) Affected individual from nonfamilial case #041. Journal of Investigative Dermatology 2016 136, 1097-1105DOI: (10.1016/j.jid.2016.01.037) Copyright © 2016 The Authors Terms and Conditions

Figure 5 Haplotype analysis of affected individuals and heterozygous carriers of c.712G>T mutation in keratin 25 (KRT25) gene. Chromosomes linked to the mutation are highlighted in red. Wild-type paternal chromosomes are in blue, whereas wild-type maternal chromosomes are colored in green. Unknown haplotype is shown as a thick black bar. Contiguous homozygous regions of ancestral haplotype are boxed. (a) Haplotypes in family #002 including a proband and her affected sister. (b) Haplotypes in family #015 of heterozygous carriers. (c) Haplotypes in family #040 of heterozygous carriers. (d) Haplotype analysis in affected individual #041. Journal of Investigative Dermatology 2016 136, 1097-1105DOI: (10.1016/j.jid.2016.01.037) Copyright © 2016 The Authors Terms and Conditions

Figure 6 The mutation p.Val238Leu leads to the disruption of keratin intermediate filament formation in HaCaT cells. (a) Results of western blots (WBs). Either wild-type (Wt) or mutant (V238L) K25 proteins with an N-terminal Flag-tag were overexpressed in HaCaT cells, and the cell lysate was used for WBs with an anti-Flag antibody. Note that there were no significant differences in expression levels between the K25-Wt and the -V238L proteins. β-Actin was used as a loading control. (b) Ratio of keratin intermediate filament (KIF) disruption upon overexpression of K25-Wt or -V238L proteins. (c–k) Results of indirect immunofluorescence. (c–e) Ectopically expressed K25-Wt protein formed a KIF network via heterodimerization with endogenous K5 protein, whereas the K25-V238L protein showed a partial effect on KIF network disruption. (f–h) The K25-V238L protein formed aggregates with K5 protein around the nuclei and damaged the KIF network in 60% of K25-V238L cells. (i–k) At the same time, 40% of K25-V238L cells showed the possibility of KIF formation. Scale bar = 20 μm (c). Journal of Investigative Dermatology 2016 136, 1097-1105DOI: (10.1016/j.jid.2016.01.037) Copyright © 2016 The Authors Terms and Conditions