Hypotrichosis simplex of the scalp is associated with nonsense mutations in CDSN encoding corneodesmosin

Levy‐Nissenbaum, Etgar; Betz, Regina C.; Frydman, Moshe; Simon, Michel; Lahat, Hadas; Bakhan, T.; Goldman, Boleslaw; Bygum, Anette; Pierick, Monika; Hillmer, Axel M.; Jonca, Nathalie; Toribio, Jaime; Kruse, Roland; Dewald, Georg; Cichon, Sven; Kubisch, Christian; Guerrin, Marina; Serre, Guy; Nöthen, Markus M.; Pras, Elon

doi:10.1038/ng1163

Cited by 165 publications

(140 citation statements)

References 14 publications

Supporting

Mentioning

132

Contrasting

Unclassified

Order By: Relevance

“…These mutations lead to a dominant hair disorder (hypotrichosis simplex of the scalp), implying that CDSN plays a role in hair-follicle growth and maintenance (Levy-Nissenbaum et al 2003). So far, no homozygous CDSN/Cdsn mutants have been reported in humans or mice.…”

Section: Resultsmentioning

confidence: 99%

“…Mutations that produce truncated forms of CDSN have been described in humans (Levy-Nissenbaum et al 2003). These mutations lead to a dominant hair disorder (hypotrichosis simplex of the scalp), implying that CDSN plays a role in hair-follicle growth and maintenance (Levy-Nissenbaum et al 2003).…”

Section: Resultsmentioning

confidence: 99%

“…Another extracellular component with a less well-defined function is corneodesmosin (CDSN) (Simon et al , 2001). Human CDSN is a 52-56-kDa glycoprotein expressed in the upper spinous and granular layers of normal skin, and in the inner root sheath of hair follicles (Levy-Nissenbaum et al 2003). This protein is secreted into the intercellular space and becomes an extracellular component of desmosomes in the granular layer and of corneodesmosomes (corneocyte-specific desmosomes) in the SC (Simon et al , 2001.…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5^-/- mice

Yang

Liang²,

Koch³

et al. 2004

Genes Dev.

103

View full text Add to dashboard Cite

Netherton syndrome (NS) is a human autosomal recessive skin disease caused by mutations in the SPINK5 gene, which encodes the putative proteinase inhibitor LEKTI. We have generated a transgenic mouse line with an insertional mutation that inactivated the mouse SPINK5 ortholog. Mutant mice exhibit fragile stratum corneum and perinatal death due to dehydration. Our analysis suggests that the phenotype is a consequence of desmosomal fragility associated with premature proteolysis of corneodesmosin, an extracellular desmosomal component. Our mouse mutant provides a model system for molecular studies of desmosomal stability and keratinocyte adhesion, and for designing therapeutic strategies to treat NS.Supplemental material is available at http://www.genesdev.org.Received June 17, 2004; revised version accepted August 6, 2004. Netherton Syndrome (NS) (MIM 256500) is a severe, recessively inherited skin disease in humans with high neonatal lethality. It is characterized by ichthyosiform erythroderma, atopic dermatitis, bamboo hair, skin barrier defects, and elevated IgE levels in survivors (Krafchik and Toole 1983;Judge et al. 1994). Mutations have been identified in the SPINK5 (serine proteinase inhibitor Kazal type 5) gene of NS patients (Chavanas et al. 2000;Sprecher et al. 2001;Walley et al. 2001;Bitoun et al. 2002;Komatsu et al. 2002). SPINK5 encodes LEKTI (lympho-epithelial Kazal-type-related inhibitor), which is a putative proteinase inhibitor that contains an N-terminal signal peptide and 15 domains with high internal homology (Magert et al. 1999). Each domain has four conserved cysteines. Domains 2 and 15 possess two additional cysteines, which make them typical Kazal-type proteinase inhibitor domains (Magert et al. 1999). LEKTI exhibits proteinase inhibitor activity in vitro (Magert et al. 1999;Komatsu et al. 2002;Walden et al. 2002;Mitsudo et al. 2003). In NS patients, loss or reduction of LEKTI activity is presumed to result in elevated proteolytic activity in the suprabasal epidermis, leading to erythroderma and skin-barrier defects. However, the specific proteins that are targeted for degradation in these patients have not been identified. We describe here a Spink5 mutant mouse line that shows severe skin defects associated with desmosomal fragility, and thus, provides insights into the molecular pathogenesis of NS and a novel model system for studies of keratinocyte adhesion. Results and DiscussionTransgenic mouse line OVE1498 was generated by coinjection of a tyrosinase-tagged (Yokoyama et al. 1990) Sleeping Beauty transposon (Ivics et al. 1997) (termed pT-Tybs-3ЈE) along with PGK2-SB10 (Ivics et al. 1997) (see Supplementary Fig. S1) into inbred FVB/N embryos. The transgenic founder and its transgenic F1 offspring were phenotypically normal and showed no evidence for transposition of the transgene(s) (data not shown). When transgenic F1 mice were intercrossed, ∼25% of the newborn offspring developed severe skin blistering and water barrier defects, leading to death within several hours after birth ...

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5^-/- mice

Yang

Liang²,

Koch³

et al. 2004

Genes Dev.

103

View full text Add to dashboard Cite

show abstract

“…Although Alu sequences inserted in the opposite directions have been found to be more prone to illegitimate recombination when they are less than 20 bp apart from each other Mutations in the CDSN gene in humans have been originally identified in patients with autosomal dominant hypotrichosis simplex of the scalp (HSS) (7). To date, all mutations responsible for HSS have been reported to be heterozygous nonsense mutations, namely p.Gln200X, p.Gln209X, p.Gln215X and p.Tyr239X, all of which lead to truncated CDSN proteins.…”

Section: Discussionmentioning

confidence: 99%

Alu‐mediated large deletion of the CDSN gene as a cause of peeling skin disease

et al. 2013

View full text Add to dashboard Cite

Peeling skin disease (PSD) is an autosomal recessive skin disorder caused by mutations in CDSN and is characterized by superficial peeling of the upper epidermis.Corneodesmosin (CDSN) is a major component of corneodesmosomes that plays an important role in maintaining epidermis integrity. Herein, we report a patient with PSD caused by a novel homozygous large deletion in the 6p21.3 region encompassing the CDSN gene, which abrogates CDSN expression. Several genes including C6orf15, PSORS1C1, PSORS1C2, CCHCR1, and TCF19 were also deleted, however, the patient showed only clinical features typical of PSD. The deletion size was 59.1 kb. Analysis of the sequence surrounding the breakpoint showed that both of the telomeric and centromeric breakpoints existed within Alu-S sequences that were oriented in opposite directions. These results suggest an Alu-mediated recombination event as the mechanism underlying the deletion in our patient.

show abstract

“…Intriguingly, the only monogenic disease associated with mutations in CDSN that has been identified so far revealed a hair phenotype and did not affect the epidermis. Indeed, nonsense mutations in CDSN were found to be responsible for a rare autosomal dominant disease, hypotrichosis simplex of the scalp (HSS; OMIM 146520) [44]. Affected individuals experience progressive loss of scalp hairs beginning in the middle of the first decade and almost complete baldness by the third decade.…”

Section: Cdsn and Human Diseasesmentioning

confidence: 99%

Corneodesmosin: Structure, Function and Involvement in Pathophysiology

Jonca¹,

Caubet²,

Guerrin³

et al. 2010

TODJ

Self Cite

View full text Add to dashboard Cite

Corneodesmosin (CDSN) was identified in the early 90 th by raising monoclonal antibodies against human plantar stratum corneum. It is a protein specific to desmosomes that will undergo transformation into corneodesmosomes, i.e. in man, desmosomes of the epidermis, of the three epithelial layers of the inner root sheath of the hair follicles and of the hard palate epithelium. After its secretion by granular keratinocytes via the lamellar bodies, CDSN is incorporated into the desmoglea of the desmosomes shortly before their transformation into corneodesmosomes. CDSN displays adhesive properties, mostly attributable to its N-terminal glycine-rich domain, and is sequentially proteolyzed as corneocytes migrate towards the skin surface. The recent inactivation of Cdsn in mice induced a lethal epidermal barrier disruption and hair follicle degeneration related to desmosome dysfunction, confirming the essential role of the protein in epidermis and hair follicle integrity. CDSN is located on chromosome 6, in the major psoriasis susceptibility locus PSORS1. Intriguingly, the only monogenic disease identified so far associated with nonsense mutations in CDSN, leading to the formation of a truncated protein, is a rare autosomal dominant disease, hypotrichosis simplex of the scalp. In this review, we expose data from the discovery of the protein to the most recent findings related to the relationship between its structure and function. In particular, the important benefits of mouse models and human diseases for the comprehension of CDSN role in the epidermis and hair follicles are reported in details.

show abstract

Hypotrichosis simplex of the scalp is associated with nonsense mutations in CDSN encoding corneodesmosin

Cited by 165 publications

References 14 publications

Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5^-/- mice

Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5^-/- mice

Alu‐mediated large deletion of the CDSN gene as a cause of peeling skin disease

Corneodesmosin: Structure, Function and Involvement in Pathophysiology

Contact Info

Product

Resources

About

Hypotrichosis simplex of the scalp is associated with nonsense mutations in CDSN encoding corneodesmosin

Cited by 165 publications

References 14 publications

Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5-/- mice

Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5-/- mice

Alu‐mediated large deletion of the CDSN gene as a cause of peeling skin disease

Corneodesmosin: Structure, Function and Involvement in Pathophysiology

Contact Info

Product

Resources

About

Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5^-/- mice

Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5^-/- mice