Loss-of-Function Mutations in HOXC13 Cause Pure Hair and Nail Ectodermal Dysplasia

Lin, Zhimiao; Chen, Quan; Shi, Lei; Lee, Ming Yang; Giehl, Kathrin; Tang, Zhanli; Wang, Huijun; Zhang, Jie; Yin, Jinghua; Wu, Lingshen; Xiao, Ruo; Liu, Xuanzhu; Dai, Lanlan; Zhu, Xuejun; Li, Ruoyu; Betz, Regina C.; Zhang, Xue; Yong, Yang

doi:10.1016/j.ajhg.2012.08.029

Cited by 69 publications

(71 citation statements)

References 38 publications

(31 reference statements)

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“…It is well recognized that specific gene mutations and altered proteins are linked to specific forms of skin diseases, such as ichthyosis, reflecting abnormal squamous differentiation and acantholytic disorders, including pemphigus with epidermal blistering at different levels. Several genes with elevated expression in skin and specific expression patterns in different epidermal layers have earlier been linked to specific forms of skin disease; e.g., (i) KRT15 (alopecia) (Al-Refu 2012) and COL17A1 (bullous pemphigoid and epidermolysis bullosa) (Powell et al 2005) expressed in the basal layer; (ii) FLG (ichthyosis vulgaris (Thyssen et al 2013), which is expressed in the granular layer; (iii) KLK5 (rosacea) (Meyer-Hoffert and Schroder 2011), which is expressed in stratum corneum; and (iv) HOXC13 (ectodermal dysplasia) (Lin et al 2012), which is expressed in hair follicles. Although specific expression patterns do not per se provide functional data, clues to function and possible involvement in disease are given.…”

Section: Discussionmentioning

confidence: 99%

Expression of Human Skin-Specific Genes Defined by Transcriptomics and Antibody-Based Profiling

Edqvist

Fagerberg

Hallström

et al. 2014

J Histochem Cytochem.

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To increase our understanding of skin, it is important to define the molecular constituents of the cell types and epidermal layers that signify normal skin. We have combined a genome-wide transcriptomics analysis, using deep sequencing of mRNA from skin biopsies, with immunohistochemistry-based protein profiling to characterize the landscape of gene and protein expression in normal human skin. The transcriptomics and protein expression data of skin were compared to 26 (RNA) and 44 (protein) other normal tissue types. All 20,050 putative protein-coding genes were classified into categories based on patterns of expression. We found that 417 genes showed elevated expression in skin, with 106 genes expressed at least five-fold higher than that in other tissues. The 106 genes categorized as skin enriched encoded for well-known proteins involved in epidermal differentiation and proteins with unknown functions and expression patterns in skin, including the C1orf68 protein, which showed the highest relative enrichment in skin. In conclusion, we have applied a genome-wide analysis to identify the human skin-specific proteome and map the precise localization of the corresponding proteins in different compartments of the skin, to facilitate further functional studies to explore the molecular repertoire of normal skin and to identify biomarkers related to various skin diseases.

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Section: Discussionmentioning

confidence: 99%

Expression of Human Skin-Specific Genes Defined by Transcriptomics and Antibody-Based Profiling

Edqvist

Fagerberg

Hallström

et al. 2014

J Histochem Cytochem.

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“…This abundant expression of keratin 85 can explain the severe hair and nail phenotype that is observed in this disorder. The same phenotypes have recently been associated with mutations in HOXC13, which regulates, directly or indirectly via the FOXN1 transcription factor, hair keratins, keratin-associated proteins and desmosomal cadherins [22]. Similar clinical findings were also observed in a Pakistani family with an autosomal recessive inheritance pattern, but with a relatively mild clinical expression.…”

Section: Keratin Disordersmentioning

confidence: 58%

Molecular Genetics of Alopecias

Ramot¹,

Zlotogorski²

2015

Alopecias - Practical Evaluation and Management

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Recent developments in research methods and techniques, such as whole-exome and -genome sequencing, have substantially improved our understanding of genetic conditions. Special progress has been made in the field of genotrichoses, or hereditary hair diseases, a field that has been obscure for many years. The underlying genes for many of the monogenic hair diseases are now known. Additionally, complex analyses of large cohorts of patients have given us the first clues to the genes associated with polygenic hair disorders, such as androgenetic alopecia and alopecia areata. Thanks to these major findings, the sophisticated regulation of the morphogenesis, development and growth of hair follicles has begun to be revealed, and new players in this delicate molecular interplay have been exposed.

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“…Hoxc13 was reported to be highly expressed in the tail, limbs, and nails in early embryos (95)(96)(97). Hoxc13 deficiency in mice and humans causes external hair loss and nail defects, whereas overexpression of Hoxc13 in mice results in ulceration and alopecia (95)(96)(97)(98)(99)(100). Our studies showed that both HOXA1 and HOXC13 play important roles in YAP-regulated epithelial progenitor cell proliferation.…”

Section: Discussionmentioning

confidence: 71%

YAP Regulates the Expression of Hoxa1 and Hoxc13 in Mouse and Human Oral and Skin Epithelial Tissues

Liu

Zhao

Lin

et al. 2015

Molecular and Cellular Biology

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c Yes-associated protein (YAP) is a Hippo signaling transcriptional coactivator that plays pivotal roles in stem cell proliferation, organ size control, and tumor development. The downstream targets of YAP have been shown to be highly context dependent. In this study, we used the embryonic mouse tooth germ as a tool to search for the downstream targets of YAP in ectoderm-derived tissues. Yap deficiency in the dental epithelium resulted in a small tooth germ with reduced epithelial cell proliferation. We compared the gene expression profiles of embryonic day 14.5 (E14.5) Yap conditional knockout and YAP transgenic mouse tooth germs using transcriptome sequencing (RNA-Seq) and further confirmed the differentially expressed genes using real-time PCR and in situ hybridization. We found that YAP regulates the expression of Hoxa1 and Hoxc13 in oral and dental epithelial tissues as well as in the epidermis of skin during embryonic and adult stages. Sphere formation assay suggested that Hoxa1 and Hoxc13 are functionally involved in YAP-regulated epithelial progenitor cell proliferation, and chromatin immunoprecipitation (ChIP) assay implies that YAP may regulate Hoxa1 and Hoxc13 expression through TEAD transcription factors. These results provide mechanistic insights into abnormal YAP activities in mice and humans. Y es-associated protein (YAP) is a key transcriptional coactivator of the Hippo signaling pathway that plays pivotal roles in stem/progenitor cell proliferation and organ size control (1-11). YAP has also been shown to be a candidate oncogene in the development and progression of multiple human cancers (12-14). The activity of YAP is negatively regulated by its upstream kinase cascade (MstI/2, Sav1, Lats1/2, and Mob1), which leads to the phosphorylation and subsequent degradation of YAP and its paralog TAZ. Inhibition of Hippo signaling relieves YAP and TAZ, which can then translocate into the nucleus. In the nucleus, YAP or TAZ associates with TEAD or other transcription factors to activate the transcription of its target genes (15-18). Conventional knockout of Yap in mice causes early embryonic lethality due to defects in yolk sac vasculogenesis (19). Overexpression of YAP results in enlarged organ size in Drosophila and in mice with profound cell proliferation and inhibition of apoptosis (1,2,7,11, 20). In addition, YAP also plays a critical role in maintaining mouse embryonic stem cell pluripotency and regulating tissue-specific progenitor cells (21).Although the core components of the Hippo pathway are highly conserved between Drosophila and mammalian systems, the transcriptional outputs differ greatly depending on when and where the pathway is deployed. For example, overexpression of YAP in the mouse small intestine leads to Notch-dependent hyperplasia and loss of terminally differentiated cell types but does not appreciably increase the overall size of the organ (1). In Drosophila, the YAP ortholog Yki induces the expression of cycE, diap1, and bantam microRNA (11, 22). In mammalian cells, YAP induces ...

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Loss-of-Function Mutations in HOXC13 Cause Pure Hair and Nail Ectodermal Dysplasia

Cited by 69 publications

References 38 publications

Expression of Human Skin-Specific Genes Defined by Transcriptomics and Antibody-Based Profiling

Expression of Human Skin-Specific Genes Defined by Transcriptomics and Antibody-Based Profiling

Molecular Genetics of Alopecias

YAP Regulates the Expression of Hoxa1 and Hoxc13 in Mouse and Human Oral and Skin Epithelial Tissues

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