Hypotrichosis with juvenile macular dystrophy is caused by a mutation in CDH3, encoding P-cadherin

Sprecher, Eli; Bergman, Reuven; Richard, Gabriele; Lurie, Raziel; Shalev, Stavit A.; Peng, Dan; Shalata, Adel; Anbinder, Yefim; Leibu, Rina; Perlman, Ido; Cohen, Nadine; Szargel, Raymonde

doi:10.1038/ng716

Cited by 161 publications

(151 citation statements)

References 12 publications

Supporting

Mentioning

143

Contrasting

Unclassified

Order By: Relevance

“…Recent advances in molecular genetics have revealed that two recessively inherited human diseases, HJMD and EEM syndrome, are caused by mutations in the CDH3 gene, encoding P-cadherin (Sprecher et al, 2001;Kjaer et al, 2005). In this study, we identified five consanguineous Pakistani families (Families 1-5) affected with either HJMD or EEM syndrome and found mutations in the CDH3 in all five families.…”

Section: Discussion P-cadherin Mutations Cause Hjmd or Eem Syndrome Imentioning

confidence: 97%

“…9). Nevertheless, in HJMD families, all affected individuals have hair and eye involvement only (Sprecher et al, 2001;Indelman et al, 2002;Indelman et al, 2003;Indelman et al, 2005;Indelman et al, 2007). Similarly, in EEM families, all affected individuals show not only hair and eye phenotype but also hand/foot involvement (Kjaer et al, 2005).…”

Section: Research Articlementioning

confidence: 99%

“…Recessively inherited mutations in the human CDH3 gene were identified in affected individuals with hypotrichosis with juvenile macular dystrophy (HJMD) characterized by congenital sparse hair and early blindness due to macular dystrophy of the retina (Sprecher et al, 2001;Indelman et al, 2002;Indelman et al, 2003;Indelman et al, 2005;Indelman et al, 2007). More recently, mutations in the CDH3 were also reported to cause another autosomal recessive human disease in two families: ectodermal dysplasia, ectrodactyly and macular dystrophy (EEM syndrome) (Kjaer et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

P-cadherin is a p63 target gene with a crucial role in the developing human limb bud and hair follicle

et al. 2008

View full text Add to dashboard Cite

*P-cadherin is a member of the classical cadherin family that forms the transmembrane core of adherens junctions. Recently, mutations in the P-cadherin gene (CDH3) have been shown to cause two inherited diseases in humans: hypotrichosis with juvenile macular dystrophy (HJMD) and ectodermal dysplasia, ectrodactyly, macular dystrophy (EEM syndrome). The common features of both diseases are sparse hair and macular dystrophy of the retina, while only EEM syndrome shows the additional finding of split hand/foot malformation (SHFM). We identified five consanguineous Pakistani families with either HJMD or EEM syndrome, and detected pathogenic mutations in the CDH3 gene of all five families. In order to define the role of P-cadherin in hair follicle and limb development, we performed expression studies on P-cadherin in the mouse embryo, and demonstrated the predominant expression of P-cadherin not only in the hair follicle placode, but also at the apical ectodermal ridge (AER) of the limb bud. Based on the evidence that mutations in the p63 gene also result in hypotrichosis and SHFM, and that the expression patterns of p63 and P-cadherin overlap in the hair follicle placode and AER, we postulated that CDH3 could be a direct transcriptional target gene of p63. We performed promoter assays and ChIP, which revealed that p63 directly interacts with two distinct regions of the CDH3 promoter. We conclude that P-cadherin is a newly defined transcriptional target gene of p63, with a crucial role in hair follicle morphogenesis as well as the AER during limb bud outgrowth in humans, whereas it is not required for either in mice.

show abstract

Section: Discussion P-cadherin Mutations Cause Hjmd or Eem Syndrome Imentioning

confidence: 97%

Section: Research Articlementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

P-cadherin is a p63 target gene with a crucial role in the developing human limb bud and hair follicle

et al. 2008

View full text Add to dashboard Cite

show abstract

“…CDH3 gene mutations have been shown to cause P-cadherin functional inactivation, leading to developmental defects associated with two inherited diseases in humans: 1) hypotrichosis with juvenile macular dystrophy (HJMD) and 2) ectodermal dysplasia, ectrodactyly, and macular dystrophy (EEM syndrome). The common features of both diseases are sparse hair and macular dystrophy of the retina, while only EEM syndrome shows the additional finding of split hand/foot malformation (SHFM) (Kjaer et al, 2005, Sprecher et al, 2001. No defects were described for these conditions, concerning the human mammary development, or other epithelial bud structures.…”

Section: B Amentioning

confidence: 99%

P-cadherin role in normal breast development and cancer

Albergaria

Ribeiro²,

Vieira³

et al. 2011

Int. J. Dev. Biol.

View full text Add to dashboard Cite

P-cadherin is a cell-cell adhesion molecule, whose expression is highly associated with undifferentiated cells in normal adult epithelial tissues, as well as with poorly differentiated carcinomas. Its expression has been already reported in human embryonic stem cells and it is presumed to be a marker of stem or progenitor cells of some epithelial tissues. In normal breast, P-cadherin has an essential role during ductal mammary branching, being expressed by the monolayer of epithelial cap cells at the end buds. In mature mammary tissue, its expression is restricted to the myoepithelium; it has been postulated that it may also be present in early luminal progenitor cells. In breast cancer, P-cadherin is frequently overexpressed in high-grade tumours, being a well-established indicator of poor patient prognosis. It has been reported as an important inducer of cancer cell migration and invasion, with underlying molecular mechanisms involving the signalling mediated by its juxtamembrane domain, the secretion of matrix metalloproteases to the extracellular media, and the cleavage of a P-cadherin soluble form with pro-invasive activity. Intracellularly, this protein interferes with the endogenous cadherin/catenin complex, inducing p120-catenin delocalization to the cytoplasm, and the consequent activation of Rac1/Cdc42 and associated alterations in the actin cytoskeleton. Considering P-cadherin's role in cancer cell invasion and metastasis formation, a humanized monoclonal antibody was recently produced to antagonize P-cadherin-associated signalling pathways, which is currently under Phase I clinical trials. In this review, the most important findings about the role of P-cadherin in normal breast development and cancer will be illustrated and discussed, with emphasis on the most recent data.

show abstract

“…Alternatively, disrupted adhesion between P-cadherin-negative myoepithelial cells might allow access of epithelial cells to the basement membrane and signals it might initiate. A human mutation in the P-cadherin gene producing a truncated, nonmembrane bound protein results in eye and hair defects, but no reported mammary gland abnormalities [Sprecher et al, 2001]. P-cadherin may play a role in the mammary gland besides providing an adhesion mechanism to the myoepithelium.…”

Section: Cadherins and Catenins In The Normal Mammary Glandmentioning

confidence: 99%

Cadherins and the mammary gland

Knudsen

Wheelock

2005

J. Cell. Biochem.

View full text Add to dashboard Cite

Cadherin cell-cell adhesion proteins are critical for the formation of tissues from single cells. E-and P-cadherin play important roles in the architecture and function of the normal mammary gland. In breast cancers, the expression, or lack thereof, of E-cadherin can differentiate tumor types, whereas the misexpression of either P-cadherin or N-cadherin can be a marker of poor prognosis or increased malignancy, respectively. Additional research is needed to more precisely define the roles of both classical and desmosomal cadherins and their downstream signaling events, in the development and malignant behavior of breast cancers. J. Cell. Classical and desmosomal cadherins mediate cell-cell adhesion and are members of the larger cadherin protein family. They are single-pass transmembrane proteins whose extracellular domain promotes cell-cell adhesion, while the intracellular domain interacts with cytoplasmic proteins, including the a-, b-, g-catenins (also known as plakoglobin) and p120 in the case of classical cadherins. a-and b-catenin (alternatively plakoglobin) link classical cadherins directly and indirectly to the actin cytoskeleton, whereas plakoglobin, desmoplakins, and plakophilins link desmosomal cadherins to the intermediate filament cytoskeleton. By virtue of their homophilic interaction and cell-type specific expression, the classical cadherins initiate cell-cell adhesion and promote cell sorting, whereas the desmosomal cadherins provide added strength to cell-cell interactions. The p120 catenin is thought to regulate clustering of classical cadherins in the plane of the membrane and to regulate the strength of cadherin cell adhesion in both positive and negative ways. In addition to playing important roles in cell adhesion, p120 and b-catenin interact with nuclear

show abstract

Hypotrichosis with juvenile macular dystrophy is caused by a mutation in CDH3, encoding P-cadherin

Cited by 161 publications

References 12 publications

P-cadherin is a p63 target gene with a crucial role in the developing human limb bud and hair follicle

P-cadherin is a p63 target gene with a crucial role in the developing human limb bud and hair follicle

P-cadherin role in normal breast development and cancer

Cadherins and the mammary gland

Contact Info

Product

Resources

About