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Abstract

TP63 plays an essential role in the development of epidermis and skin appendages. Mutations in TP63 can give rise to a series of syndromes characterized by various combinations of ectodermal dysplasia, limb malformations, and orofacial clefting in many populations. To test whether TP63 is the disease-causative gene for these phenotypes in Chinese, we recruited two Chinese Ectrodactyly-Ectodermal-dysplasia-Cleft lip/palate syndrome (EEC) cases and a Limb-Mammary-Syndrome (LMS) patient to carry out TP63 gene sequencing. Three missense mutation, c.812G>C (Ser271Thr), c.611G>A (Arg204Gln), and c.680G>A (Arg227Gln), which lead to the substitution of highly conserved amino acids in the DNA-binding domain of TP63, were identified. These mutations were predicted to disrupt DNA-binding specificity and affinity. To our knowledge, this is the first report of EEC and LMS syndromes in individuals of Chinese descent. Analysis of our data demonstrated that TP63 is critical for the development of ectoderm in humans.

Keywords

ectrodactyly,ectodermal dysplasia,and cleft lip/palate syndrome (EEC)limb-mammary syndrome (LMS)protein modeling DNA binding domain

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References

Barrow

van Bokhoven

Daack-Hirsch

Andersen

van Beersum

Gorlin

. (2002). Analysis of the p63 gene in classical EEC syndrome, related syndromes, and non-syndromic orofacial clefts. J Med Genet 39:559-566.

Bertola

Kim

Albano

Scheffer

Meijer

van Bokhoven

(2004). Molecular evidence that AEC syndrome and Rapp-Hodgkin syndrome are variable expression of a single genetic disorder. Clin Genet 66:79-80.

Brunner

Hamel

Van Bokhoven

(2002a). The p63 gene in EEC and other syndromes. J Med Genet 39:377-381.

Brunner

Hamel

Van Bokhoven Hv

(2002b). p63 gene mutations and human developmental syndromes. Am J Med Genet A 112:284-290.

Celli

Duijf

Hamel

Bamshad

Kramer

Smits

. (1999). Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell 99:143-153.

Chan

Harper

Mellerio

McGrath

(2004). ADULT ectodermal dysplasia syndrome resulting from the missense mutation R298Q in the p63 gene. Clin Exp Dermatol 29:669-672.

Cho

Gorina

Jeffrey

Pavletich

(1994). Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science 265:346-355.

Dianzani

Garelli

Gustavsson

Carando

Gustafsson

Dahl

. (2003). Rapp-Hodgkin and AEC syndromes due to a new frameshift mutation in the TP63 gene. J Med Genet 40:e133.

Duijf

Vanmolkot

Propping

Friedl

Krieger

McKeon

. (2002). Gain-of-function mutation in ADULT syndrome reveals the presence of a second transactivation domain in p63. Hum Mol Genet 11:799-804.

10.

Fan

Shi

Yin

Hua

Song

. (2008). Mutations in the EDA gene are responsible for X-linked hypohidrotic ectodermal dysplasia and hypodontia in Chinese kindreds. Eur J Oral Sci 116:412-417.

11.

Ianakiev

Kilpatrick

Toudjarska

Basel

Beighton

Tsipouras

(2000). Split-hand/split-foot malformation is caused by mutations in the p63 gene on 3q27. Am J Hum Genet 67:59-66.

12.

Kannu

Savarirayan

Ozoemena

White

McGrath

(2006). Rapp-Hodgkin ectodermal dysplasia syndrome: the clinical and molecular overlap with Hay-Wells syndrome. Am J Med Genet A 140:887-891.

13.

Kantaputra

Hamada

Kumchai

McGrath

(2003). Heterozygous mutation in the SAM domain of p63 underlies Rapp-Hodgkin ectodermal dysplasia. J Dent Res 82:433-437.

14.

Keyes

Vogel

Koster

Guo

Petherbridge

. (2006). p63 heterozygous mutant mice are not prone to spontaneous or chemically induced tumors. Proc Natl Acad Sci USA 103:8435-8440.

15.

Kosaki

Ohashi

Yoshihashi

Suzuki

Kosaki

(2001) A de novo mutation (R279C) in the p63 gene in a patient with EEC syndrome. Clin Genet 60:314-315.

16.

Leoyklang

Siriwan

Shotelersuk

(2006). A mutation of the p63 gene in non-syndromic cleft lip. J Med Genet 43:e28.

17.

McGrath

Duijf

Doetsch

Irvine

de Waal

Vanmolkot

. (2001). Hay-Wells syndrome is caused by heterozygous missense mutations in the SAM domain of p63. Hum Mol Genet 10:221-229.

18.

Mikkola

(2007). p63 in skin appendage development. Cell Cycle 6:285-290.

19.

Mills

Zheng

Wang

Vogel

Roop

Bradley

(1999). p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 398:708-713.

20.

Ray

Marazita

Pathak

Beever

Cooper

Goldstein

. (2004) TP63 mutation and clefting modifier genes in an EEC syndrome family. Clin Genet 66:217-222.

21.

Rinne

Hamel

van Bokhoven

Brunner

(2006). Pattern of p63 mutations and their phenotypes—update. Am J Med Genet A 140:1396-1406.

22.

Rinne

Brunner

van Bokhoven

(2007). p63-associated disorders. Cell Cycle 6:262-268.

23.

Roelfsema

Cobben

(1996). The EEC syndrome: a literature study. Clin Dysmorphol 5:115-127.

24.

van Bokhoven

Brunner

(2002). Splitting p63. Am J Hum Genet 71:1-13.

25.

van Bokhoven

Jung

Smits

van Beersum

Ruschendorf

van Steensel

. (1999). Limb mammary syndrome: a new genetic disorder with mammary hypoplasia, ectrodactyly, and other hand/foot anomalies maps to human chromosome 3q27. Am J Hum Genet 64:538-546.

26.

van Bokhoven

Hamel

Bamshad

Sangiorgi

Gurrieri

Duijf

. (2001). p63 gene mutations in EEC syndrome, limb-mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation. Am J Hum Genet 69:481-492.

27.

Yang

Schweitzer

Sun

Kaghad

Walker

Bronson

. (1999) p63 is essential for regenerative proliferation in limb, cranio-facial and epithelial development. Nature 398:714-718.

28.

Jin

Shi

Fan

Song

Fan

. (2005). Identification of novel mutations of IRF6 gene in Chinese families with Van der Woude syndrome. Int J Mol Med 16:851-856.

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TP63 Gene Mutations in Chinese P63 Syndrome Patients

Abstract

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