| Structural highlights
Disease
EDA_HUMAN Defects in EDA are the cause of ectodermal dysplasia 1, hypohidrotic, X-linked (XHED) [MIM:305100; also known as Christ-Siemens-Touraine syndrome or X-linked hypohidrotic ectodermal dysplasia (XLHED). Ectodermal dysplasia defines a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. XHED is a disease characterized by sparse hair (atrichosis or hypotrichosis), abnormal or missing teeth and the inability to sweat due to the absence of sweat glands. XHED is the most common form of over 150 clinically distinct ectodermal dysplasias.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] Defects in EDA are the cause of tooth agenesis selective X-linked type 1 (STHAGX1) [MIM:313500. A form of selective tooth agenesis, a common anomaly characterized by the congenital absence of one or more teeth. Selective tooth agenesis without associated systemic disorders has sometimes been divided into 2 types: oligodontia, defined as agenesis of 6 or more permanent teeth, and hypodontia, defined as agenesis of less than 6 teeth. The number in both cases does not include absence of third molars (wisdom teeth).[24] [25]
Function
EDA_HUMAN Seems to be involved in epithelial-mesenchymal signaling during morphogenesis of ectodermal organs. Isoform 1 binds only to the receptor EDAR, while isoform 3 binds exclusively to the receptor XEDAR.
Publication Abstract from PubMed
EDA is a tumor necrosis factor (TNF) family member, which functions together with its cognate receptor EDAR during ectodermal organ development. Mutations of EDA have long been known to cause X-linked hypohidrotic dysplasia in humans characterized by primary defects in teeth, hair and sweat glands. However, the structural information of EDA interaction with EDAR is lacking and the pathogenic mechanism of EDA variants is poorly understood. Here, we report the crystal structure of EDA C-terminal TNF homology domain bound to the N-terminal cysteine-rich domains of EDAR. Together with biochemical, cellular and mouse genetic studies, we show that different EDA mutations lead to varying degrees of ectodermal developmental defects in mice, which is consistent with the clinical observations on human patients. Our work extends the understanding of the EDA signaling mechanism, and provides important insights into the molecular pathogenesis of disease-causing EDA variants.
Structural insights into pathogenic mechanism of hypohidrotic ectodermal dysplasia caused by ectodysplasin A variants.,Yu K, Huang C, Wan F, Jiang C, Chen J, Li X, Wang F, Wu J, Lei M, Wu Y Nat Commun. 2023 Feb 11;14(1):767. doi: 10.1038/s41467-023-36367-6. PMID:36765055[26]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kere J, Srivastava AK, Montonen O, Zonana J, Thomas N, Ferguson B, Munoz F, Morgan D, Clarke A, Baybayan P, Chen EY, Ezer S, Saarialho-Kere U, de la Chapelle A, Schlessinger D. X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. Nat Genet. 1996 Aug;13(4):409-16. PMID:8696334 doi:10.1038/ng0895-409
- ↑ Monreal AW, Zonana J, Ferguson B. Identification of a new splice form of the EDA1 gene permits detection of nearly all X-linked hypohidrotic ectodermal dysplasia mutations. Am J Hum Genet. 1998 Aug;63(2):380-9. PMID:9683615 doi:S0002-9297(07)61481-5
- ↑ Bayes M, Hartung AJ, Ezer S, Pispa J, Thesleff I, Srivastava AK, Kere J. The anhidrotic ectodermal dysplasia gene (EDA) undergoes alternative splicing and encodes ectodysplasin-A with deletion mutations in collagenous repeats. Hum Mol Genet. 1998 Oct;7(11):1661-9. PMID:9736768
- ↑ Elomaa O, Pulkkinen K, Hannelius U, Mikkola M, Saarialho-Kere U, Kere J. Ectodysplasin is released by proteolytic shedding and binds to the EDAR protein. Hum Mol Genet. 2001 Apr 15;10(9):953-62. PMID:11309369
- ↑ Chen Y, Molloy SS, Thomas L, Gambee J, Bachinger HP, Ferguson B, Zonana J, Thomas G, Morris NP. Mutations within a furin consensus sequence block proteolytic release of ectodysplasin-A and cause X-linked hypohidrotic ectodermal dysplasia. Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7218-23. PMID:11416205 doi:10.1073/pnas.131076098
- ↑ Hertz JM, Norgaard Hansen K, Juncker I, Kjeldsen M, Gregersen N. A novel missense mutation (402C-->T) in exon 1 in the EDA gene in a family with X-linked hypohidrotic ectodermal dysplasia. Clin Genet. 1998 Mar;53(3):205-9. PMID:9630076
- ↑ Ferguson BM, Thomas NS, Munoz F, Morgan D, Clarke A, Zonana J. Scarcity of mutations detected in families with X linked hypohidrotic ectodermal dysplasia: diagnostic implications. J Med Genet. 1998 Feb;35(2):112-5. PMID:9507389
- ↑ Martinez F, Millan JM, Orellana C, Prieto F. X-linked anhidrotic (hypohidrotic) ectodermal dysplasia caused by a novel mutation in EDA1 gene: 406T > G (Leu55Arg) J Invest Dermatol. 1999 Aug;113(2):285-6. PMID:10469321 doi:10.1046/j.1523-1747.1999.00656.x
- ↑ Aoki N, Ito K, Tachibana T, Ito M. A novel arginine-->Serine mutation in EDA1 in a Japanese family with X-linked anhidrotic ectodermal dysplasia. J Invest Dermatol. 2000 Aug;115(2):329-30. PMID:10951256 doi:10.1046/j.1523-1747.2000.00065-1.x
- ↑ Kobielak K, Kobielak A, Roszkiewicz J, Wierzba J, Limon J, Trzeciak WH. Mutations in the EDA gene in three unrelated families reveal no apparent correlation between phenotype and genotype in the patients with an X-linked anhidrotic ectodermal dysplasia. Am J Med Genet. 2001 May 1;100(3):191-7. PMID:11343303
- ↑ Vincent MC, Biancalana V, Ginisty D, Mandel JL, Calvas P. Mutational spectrum of the ED1 gene in X-linked hypohidrotic ectodermal dysplasia. Eur J Hum Genet. 2001 May;9(5):355-63. PMID:11378824 doi:10.1038/sj.ejhg.5200635
- ↑ Paakkonen K, Cambiaghi S, Novelli G, Ouzts LV, Penttinen M, Kere J, Srivastava AK. The mutation spectrum of the EDA gene in X-linked anhidrotic ectodermal dysplasia. Hum Mutat. 2001 Apr;17(4):349. PMID:11295832 doi:10.1002/humu.33
- ↑ Schneider P, Street SL, Gaide O, Hertig S, Tardivel A, Tschopp J, Runkel L, Alevizopoulos K, Ferguson BM, Zonana J. Mutations leading to X-linked hypohidrotic ectodermal dysplasia affect three major functional domains in the tumor necrosis factor family member ectodysplasin-A. J Biol Chem. 2001 Jun 1;276(22):18819-27. Epub 2001 Mar 14. PMID:11279189 doi:10.1074/jbc.M101280200
- ↑ Vincent MC, Cossee M, Vabres P, Stewart F, Bonneau D, Calvas P. Pitfalls in clinical diagnosis of female carriers of X-linked hypohidrotic ectodermal dysplasia. Arch Dermatol. 2002 Sep;138(9):1256-8. PMID:12225002
- ↑ Hsu MM, Chao SC, Lu AC. A novel missense mutation (Gln306His) in exon 7 of the ED1 gene causing anhidrotic ectodermal dysplasia with prominent milia-like facial sebaceous papules. Br J Dermatol. 2003 Aug;149(2):443-5. PMID:12932274
- ↑ Tarpey P, Pemberton TJ, Stockton DW, Das P, Ninis V, Edkins S, Andrew Futreal P, Wooster R, Kamath S, Nayak R, Stratton MR, Patel PI. A novel Gln358Glu mutation in ectodysplasin A associated with X-linked dominant incisor hypodontia. Am J Med Genet A. 2007 Feb 15;143(4):390-4. PMID:17256800 doi:10.1002/ajmg.a.31567
- ↑ van der Hout AH, Oudesluijs GG, Venema A, Verheij JB, Mol BG, Rump P, Brunner HG, Vos YJ, van Essen AJ. Mutation screening of the Ectodysplasin-A receptor gene EDAR in hypohidrotic ectodermal dysplasia. Eur J Hum Genet. 2008 Jun;16(6):673-9. Epub 2008 Jan 30. PMID:18231121 doi:5202012
- ↑ Shimomura Y, Wajid M, Weiser J, Kraemer L, Ishii Y, Lombillo V, Bale SJ, Christiano AM. Identification of mutations in the EDA and EDAR genes in Pakistani families with hypohidrotic ectodermal dysplasia. Clin Genet. 2009 Jun;75(6):582-4. doi: 10.1111/j.1399-0004.2009.01178.x. Epub, 2009 May 5. PMID:19438931 doi:10.1111/j.1399-0004.2009.01178.x
- ↑ Gunadi, Miura K, Ohta M, Sugano A, Lee MJ, Sato Y, Matsunaga A, Hayashi K, Horikawa T, Miki K, Wataya-Kaneda M, Katayama I, Nishigori C, Matsuo M, Takaoka Y, Nishio H. Two novel mutations in the ED1 gene in Japanese families with X-linked hypohidrotic ectodermal dysplasia. Pediatr Res. 2009 Apr;65(4):453-7. doi: 10.1203/PDR.0b013e3181991229. PMID:19127222 doi:10.1203/PDR.0b013e3181991229
- ↑ Khabour OF, Mesmar FS, Al-Tamimi F, Al-Batayneh OB, Owais AI. Missense mutation of the EDA gene in a Jordanian family with X-linked hypohidrotic ectodermal dysplasia: phenotypic appearance and speech problems. Genet Mol Res. 2010 May 18;9(2):941-8. doi: 10.4238/vol9-2gmr810. PMID:20486090 doi:10.4238/vol9-2gmr810
- ↑ Cluzeau C, Hadj-Rabia S, Jambou M, Mansour S, Guigue P, Masmoudi S, Bal E, Chassaing N, Vincent MC, Viot G, Clauss F, Maniere MC, Toupenay S, Le Merrer M, Lyonnet S, Cormier-Daire V, Amiel J, Faivre L, de Prost Y, Munnich A, Bonnefont JP, Bodemer C, Smahi A. Only four genes (EDA1, EDAR, EDARADD, and WNT10A) account for 90% of hypohidrotic/anhidrotic ectodermal dysplasia cases. Hum Mutat. 2011 Jan;32(1):70-2. doi: 10.1002/humu.21384. PMID:20979233 doi:10.1002/humu.21384
- ↑ Liu Y, Yu X, Wang L, Li C, Archacki S, Huang C, Liu JY, Wang Q, Liu M, Tang Z. Mutation p.Leu354Pro in EDA causes severe hypohidrotic ectodermal dysplasia in a Chinese family. Gene. 2012 Jan 10;491(2):246-50. doi: 10.1016/j.gene.2011.10.009. Epub 2011 Oct, 10. PMID:22008666 doi:10.1016/j.gene.2011.10.009
- ↑ Piccione M, Serra G, Sanfilippo C, Andreucci E, Sani I, Corsello G. A new mutation in EDA gene in X-linked hypohidrotic ectodermal dysplasia associated with keratoconus. Minerva Pediatr. 2012 Feb;64(1):59-64. PMID:22350046
- ↑ Tao R, Jin B, Guo SZ, Qing W, Feng GY, Brooks DG, Liu L, Xu J, Li T, Yan Y, He L. A novel missense mutation of the EDA gene in a Mongolian family with congenital hypodontia. J Hum Genet. 2006;51(5):498-502. Epub 2006 Apr 1. PMID:16583127 doi:10.1007/s10038-006-0389-2
- ↑ Han D, Gong Y, Wu H, Zhang X, Yan M, Wang X, Qu H, Feng H, Song S. Novel EDA mutation resulting in X-linked non-syndromic hypodontia and the pattern of EDA-associated isolated tooth agenesis. Eur J Med Genet. 2008 Nov-Dec;51(6):536-46. doi: 10.1016/j.ejmg.2008.06.002. Epub, 2008 Jul 9. PMID:18657636 doi:10.1016/j.ejmg.2008.06.002
- ↑ Yu K, Huang C, Wan F, Jiang C, Chen J, Li X, Wang F, Wu J, Lei M, Wu Y. Structural insights into pathogenic mechanism of hypohidrotic ectodermal dysplasia caused by ectodysplasin A variants. Nat Commun. 2023 Feb 11;14(1):767. PMID:36765055 doi:10.1038/s41467-023-36367-6
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