Heterozygous MAP3K20 variants cause ectodermal dysplasia, craniosynostosis, sensorineural hearing loss, and limb anomalies.
Journal
Human genetics
ISSN: 1432-1203
Titre abrégé: Hum Genet
Pays: Germany
ID NLM: 7613873
Informations de publication
Date de publication:
07 Mar 2024
07 Mar 2024
Historique:
received:
17
11
2023
accepted:
13
02
2024
medline:
7
3
2024
pubmed:
7
3
2024
entrez:
7
3
2024
Statut:
aheadofprint
Résumé
Biallelic pathogenic variants in MAP3K20, which encodes a mitogen-activated protein kinase, are a rare cause of split-hand foot malformation (SHFM), hearing loss, and nail abnormalities or congenital myopathy. However, heterozygous variants in this gene have not been definitively associated with a phenotype. Here, we describe the phenotypic spectrum associated with heterozygous de novo variants in the linker region between the kinase domain and leucine zipper domain of MAP3K20. We report five individuals with diverse clinical features, including craniosynostosis, limb anomalies, sensorineural hearing loss, and ectodermal dysplasia-like phenotypes who have heterozygous de novo variants in this specific region of the gene. These individuals exhibit both shared and unique clinical manifestations, highlighting the complexity and variability of the disorder. We propose that the involvement of MAP3K20 in endothelial-mesenchymal transition provides a plausible etiology of these features. Together, these findings characterize a disorder that both expands the phenotypic spectrum associated with MAP3K20 and highlights the need for further studies on its role in early human development.
Identifiants
pubmed: 38451290
doi: 10.1007/s00439-024-02657-2
pii: 10.1007/s00439-024-02657-2
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIH HHS
ID : U01HG007709
Pays : United States
Organisme : NIH HHS
ID : U01HG007943
Pays : United States
Organisme : NIH HHS
ID : U01HG007709
Pays : United States
Organisme : NIH HHS
ID : U01HG007709
Pays : United States
Organisme : NIH HHS
ID : U01HG007709
Pays : United States
Organisme : NIH HHS
ID : S10-OD030246
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1HG008900
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1HG008900
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1HG008900
Pays : United States
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Adams DR, Sincan M, Fuentes Fajardo K, Mullikin JC, Pierson TM, Toro C, Boerkoel CF, Tifft CJ, Gahl WA, Markello TC (2012) Analysis of DNA sequence variants detected by high-throughput sequencing. Hum Mutat 33:599–608. https://doi.org/10.1002/humu.22035
doi: 10.1002/humu.22035
pubmed: 22290882
pmcid: 3959770
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249. https://doi.org/10.1038/nmeth0410-248
doi: 10.1038/nmeth0410-248
pubmed: 20354512
pmcid: 2855889
Ahmad I, Khan A, Noor Ul Ayan H, Budde B, Altmuller J, Korejo AA, Nurnberg G, Thiele H, Tariq M, Nurnberg P, Erdmann J (2023) A novel MAP3K20 mutation causing centronuclear myopathy-6 with fiber-type disproportion in a Pakistani family. J Hum Genet 68:107–109. https://doi.org/10.1038/s10038-022-01085-2
doi: 10.1038/s10038-022-01085-2
pubmed: 36217027
Chang Y, Lu X, Shibu MA, Dai YB, Luo J, Zhang Y, Li Y, Zhao P, Zhang Z, Xu Y, Tu ZC, Zhang QW, Yun CH, Huang CY, Ding K (2017) Structure based design of N-(3-((1H-Pyrazolo[3,4-b]pyridin-5-yl)ethynyl)benzenesulfonamides as selective leucine-zipper and sterile-alpha motif kinase (ZAK) inhibitors. J Med Chem 60:5927–5932. https://doi.org/10.1021/acs.jmedchem.7b00572
doi: 10.1021/acs.jmedchem.7b00572
pubmed: 28586211
Chen S, Francioli LC, Goodrich JK, Collins RL, Kanai M, Wang Q, Alfoldi J, Watts NA, Vittal C, Gauthier LD, Poterba T, Wilson MW, Tarasova Y, Phu W, Grant R, Yohannes MT, Koenig Z, Farjoun Y, Banks E, Donnelly S, Gabriel S, Gupta N, Ferriera S, Tolonen C, Novod S, Bergelson L, Roazen D, Ruano-Rubio V, Covarrubias M, Llanwarne C, Petrillo N, Wade G, Jeandet T, Munshi R, Tibbetts K, C. Genome Aggregation Database, O’Donnell-Luria A, Solomonson M, Seed C, Martin AR, Talkowski ME, Rehm HL, Daly MJ, Tiao G, Neale BM, MacArthur DG, Karczewski KJ (2024) A genomic mutational constraint map using variation in 76,156 human genomes. Nature 625:92–100. https://doi.org/10.1038/s41586-023-06045-0
doi: 10.1038/s41586-023-06045-0
pubmed: 38057664
Collins RL, Brand H, Karczewski KJ, Zhao X, Alfoldi J, Francioli LC, Khera AV, Lowther C, Gauthier LD, Wang H, Watts NA, Solomonson M, O’Donnell-Luria A, Baumann A, Munshi R, Walker M, Whelan CW, Huang Y, Brookings T, Sharpe T, Stone MR, Valkanas E, Fu J, Tiao G, Laricchia KM, Ruano-Rubio V, Stevens C, Gupta N, Cusick C, Margolin L, T. Genome Aggregation Database Production, C. Genome Aggregation Database, Taylor KD, Lin HJ, Rich SS, Post WS, Chen YI, Rotter JI, Nusbaum C, Philippakis A, Lander E, Gabriel S, Neale BM, Kathiresan S, Daly MJ, Banks E, MacArthur DG, Talkowski ME (2020) A structural variation reference for medical and population genetics. Nature 581:444–451. https://doi.org/10.1038/s41586-020-2287-8
doi: 10.1038/s41586-020-2287-8
pubmed: 32461652
pmcid: 7334194
Dill TL, Carroll A, Pinheiro A, Gao J, Naya FJ (2021) The long noncoding RNA Meg3 regulates myoblast plasticity and muscle regeneration through epithelial-mesenchymal transition. Development. https://doi.org/10.1242/dev.194027
doi: 10.1242/dev.194027
pubmed: 33298462
Emsley P, Lohkamp B, Scott WG, Cowtan K (2010) Features and development of Coot. Acta Crystallogr D Biol Crystallogr 66:486–501. https://doi.org/10.1107/S0907444910007493
doi: 10.1107/S0907444910007493
pubmed: 20383002
pmcid: 2852313
Evans R, O’Neill M, Pritzel A, Antroprova N, Senior A, Green T, Zidek A, Bates R, Blackwell S, Yim J, Ronneberger O, Bodenstein S, Zielinski M, Bridgland A, Potapenko A, Cowie A, Tunyasuvunakool K, Jain R, Clancy E, Kohli P, Jumper J, Hassabis D (2022) Protein complex prediction with AlphaFold-Multimer. bioRxiv 11:e0161879. https://doi.org/10.1101/2021.10.04.463034
doi: 10.1101/2021.10.04.463034
Funk CR, Huey ES, May MM, Peng Y, Michonova E, Best RG, Schwartz CE, Blenda AV (2020) Rare missense variant p.Ala505Ser in the ZAK protein observed in a patient with split-hand/foot malformation from a non-consanguineous pedigree. J Int Med Res 48:300060519879293. https://doi.org/10.1177/0300060519879293
doi: 10.1177/0300060519879293
pubmed: 32266845
Gonfloni S, Williams JC, Hattula K, Weijland A, Wierenga RK, Superti-Furga G (1997) The role of the linker between the SH2 domain and catalytic domain in the regulation and function of Src. EMBO J 16:7261–7271. https://doi.org/10.1093/emboj/16.24.7261
doi: 10.1093/emboj/16.24.7261
pubmed: 9405355
pmcid: 1170326
Guero S, Holder-Espinasse M (2019) Insights into the pathogenesis and treatment of split/hand foot malformation (cleft hand/foot). J Hand Surg Eur 44:80–87. https://doi.org/10.1177/1753193418807375
doi: 10.1177/1753193418807375
Heurtier L, Lamrini H, Chentout L, Deau MC, Bouafia A, Rosain J, Plaza JM, Parisot M, Dumont B, Turpin D, Merlin E, Moshous D, Aladjidi N, Neven B, Picard C, Cavazzana M, Fischer A, Durandy A, Stephan JL, Kracker S (2017) Mutations in the adaptor-binding domain and associated linker region of p110delta cause activated PI3K-delta syndrome 1 (APDS1). Haematologica 102:e278–e281. https://doi.org/10.3324/haematol.2017.167601
doi: 10.3324/haematol.2017.167601
pubmed: 28428270
pmcid: 5566055
Hu Z, Luo X, Zhang L, Lu F, Dong F, Monsell E, Jiang H (2012) Generation of human inner ear prosensory-like cells via epithelial-to-mesenchymal transition. Regen Med 7:663–673. https://doi.org/10.2217/rme.12.53
doi: 10.2217/rme.12.53
pubmed: 22954437
Ioannidis NM, Rothstein JH, Pejaver V, Middha S, McDonnell SK, Baheti S, Musolf A, Li Q, Holzinger E, Karyadi D, Cannon-Albright LA, Teerlink CC, Stanford JL, Isaacs WB, Xu J, Cooney KA, Lange EM, Schleutker J, Carpten JD, Powell IJ, Cussenot O, Cancel-Tassin G, Giles GG, MacInnis RJ, Maier C, Hsieh CL, Wiklund F, Catalona WJ, Foulkes WD, Mandal D, Eeles RA, Kote-Jarai Z, Bustamante CD, Schaid DJ, Hastie T, Ostrander EA, Bailey-Wilson JE, Radivojac P, Thibodeau SN, Whittemore AS, Sieh W (2016) REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet 99:877–885. https://doi.org/10.1016/j.ajhg.2016.08.016
doi: 10.1016/j.ajhg.2016.08.016
pubmed: 27666373
pmcid: 5065685
Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O, Tunyasuvunakool K, Bates R, Zidek A, Potapenko A, Bridgland A, Meyer C, Kohl SAA, Ballard AJ, Cowie A, Romera-Paredes B, Nikolov S, Jain R, Adler J, Back T, Petersen S, Reiman D, Clancy E, Zielinski M, Steinegger M, Pacholska M, Berghammer T, Bodenstein S, Silver D, Vinyals O, Senior AW, Kavukcuoglu K, Kohli P, Hassabis D (2021) Highly accurate protein structure prediction with AlphaFold. Nature 596:583–589. https://doi.org/10.1038/s41586-021-03819-2
doi: 10.1038/s41586-021-03819-2
pubmed: 34265844
pmcid: 8371605
Kahata K, Dadras MS, Moustakas A (2018) TGF-beta family signaling in epithelial differentiation and epithelial–mesenchymal transition. Cold Spring Harb Perspect Biol 10:a022194. https://doi.org/10.1101/cshperspect.a022194
doi: 10.1101/cshperspect.a022194
pubmed: 28246184
pmcid: 5749157
Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alfoldi J, Wang Q, Collins RL, Laricchia KM, Ganna A, Birnbaum DP, Gauthier LD, Brand H, Solomonson M, Watts NA, Rhodes D, Singer-Berk M, England EM, Seaby EG, Kosmicki JA, Walters RK, Tashman K, Farjoun Y, Banks E, Poterba T, Wang A, Seed C, Whiffin N, Chong JX, Samocha KE, Pierce-Hoffman E, Zappala Z, O’Donnell-Luria AH, Minikel EV, Weisburd B, Lek M, Ware JS, Vittal C, Armean IM, Bergelson L, Cibulskis K, Connolly KM, Covarrubias M, Donnelly S, Ferriera S, Gabriel S, Gentry J, Gupta N, Jeandet T, Kaplan D, Llanwarne C, Munshi R, Novod S, Petrillo N, Roazen D, Ruano-Rubio V, Saltzman A, Schleicher M, Soto J, Tibbetts K, Tolonen C, Wade G, Talkowski ME, Genome Aggregation Database C, Neale BM, Daly MJ, MacArthur DG (2020) The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581:434–443. https://doi.org/10.1038/s41586-020-2308-7
doi: 10.1038/s41586-020-2308-7
pubmed: 32461654
pmcid: 7334197
Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073–1081. https://doi.org/10.1038/nprot.2009.86
doi: 10.1038/nprot.2009.86
pubmed: 19561590
Li L, Su N, Zhou T, Zheng D, Wang Z, Chen H, Yuan S, Li W (2018) Mixed lineage kinase ZAK promotes epithelial–mesenchymal transition in cancer progression. Cell Death Dis 9:143. https://doi.org/10.1038/s41419-017-0161-x
doi: 10.1038/s41419-017-0161-x
pubmed: 29396440
pmcid: 5833348
Liu TC, Huang CJ, Chu YC, Wei CC, Chou CC, Chou MY, Chou CK, Yang JJ (2000) Cloning and expression of ZAK, a mixed lineage kinase-like protein containing a leucine-zipper and a sterile-alpha motif. Biochem Biophys Res Commun 274:811–816. https://doi.org/10.1006/bbrc.2000.3236
doi: 10.1006/bbrc.2000.3236
pubmed: 10924358
Pais LS, Snow H, Weisburd B, Zhang S, Baxter SM, DiTroia S, O’Heir E, England E, Chao KR, Lemire G, Osei-Owusu I, VanNoy GE, Wilson M, Nguyen K, Arachchi H, Phu W, Solomonson M, Mano S, O’Leary M, Lovgren A, Babb L, Austin-Tse CA, Rehm HL, MacArthur DG, O’Donnell-Luria A (2022) Seqr: a web-based analysis and collaboration tool for rare disease genomics. Hum Mutat 43:698–707. https://doi.org/10.1002/humu.24366
doi: 10.1002/humu.24366
pubmed: 35266241
pmcid: 9903206
Philippakis AA, Azzariti DR, Beltran S, Brookes AJ, Brownstein CA, Brudno M, Brunner HG, Buske OJ, Carey K, Doll C, Dumitriu S, Dyke SO, den Dunnen JT, Firth HV, Gibbs RA, Girdea M, Gonzalez M, Haendel MA, Hamosh A, Holm IA, Huang L, Hurles ME, Hutton B, Krier JB, Misyura A, Mungall CJ, Paschall J, Paten B, Robinson PN, Schiettecatte F, Sobreira NL, Swaminathan GJ, Taschner PE, Terry SF, Washington NL, Zuchner S, Boycott KM, Rehm HL (2015) The matchmaker exchange: a platform for rare disease gene discovery. Hum Mutat 36:915–921. https://doi.org/10.1002/humu.22858
doi: 10.1002/humu.22858
pubmed: 26295439
pmcid: 4610002
Priolo M (2009) Ectodermal dysplasias: an overview and update of clinical and molecular-functional mechanisms. Am J Med Genet A 149A:2003–2013. https://doi.org/10.1002/ajmg.a.32804
doi: 10.1002/ajmg.a.32804
pubmed: 19504607
Priolo M, Lagana C (2001) Ectodermal dysplasias: a new clinical-genetic classification. J Med Genet 38:579–585. https://doi.org/10.1136/jmg.38.9.579
doi: 10.1136/jmg.38.9.579
pubmed: 11546825
pmcid: 1734928
Rentzsch P, Schubach M, Shendure J, Kircher M (2021) CADD-Splice-improving genome-wide variant effect prediction using deep learning-derived splice scores. Genome Med 13:31. https://doi.org/10.1186/s13073-021-00835-9
doi: 10.1186/s13073-021-00835-9
pubmed: 33618777
pmcid: 7901104
Siismets EM, Hatch NE (2020) Cranial neural crest cells and their role in the pathogenesis of craniofacial anomalies and coronal craniosynostosis. J Dev Biol 8(3):18. https://doi.org/10.3390/jdb8030018
doi: 10.3390/jdb8030018
pubmed: 32916911
pmcid: 7558351
Sobreira N, Schiettecatte F, Valle D, Hamosh A (2015) GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat 36:928–930. https://doi.org/10.1002/humu.22844
doi: 10.1002/humu.22844
pubmed: 26220891
pmcid: 4833888
Spielmann M, Kakar N, Tayebi N, Leettola C, Nurnberg G, Sowada N, Lupianez DG, Harabula I, Flottmann R, Horn D, Chan WL, Wittler L, Yilmaz R, Altmuller J, Thiele H, van Bokhoven H, Schwartz CE, Nurnberg P, Bowie JU, Ahmad J, Kubisch C, Mundlos S, Borck G (2016) Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice. Genome Res 26:183–191. https://doi.org/10.1101/gr.199430.115
doi: 10.1101/gr.199430.115
pubmed: 26755636
pmcid: 4728371
Splinter K, Adams DR, Bacino CA, Bellen HJ, Bernstein JA, Cheatle-Jarvela AM, Eng CM, Esteves C, Gahl WA, Hamid R, Jacob HJ, Kikani B, Koeller DM, Kohane IS, Lee BH, Loscalzo J, Luo X, McCray AT, Metz TO, Mulvihill JJ, Nelson SF, Palmer CGS, Phillips JA 3rd, Pick L, Postlethwait JH, Reuter C, Shashi V, Sweetser DA, Tifft CJ, Walley NM, Wangler MF, Westerfield M, Wheeler MT, Wise AL, Worthey EA, Yamamoto S, Ashley EA, Undiagnosed Diseases N (2018) Effect of genetic diagnosis on patients with previously undiagnosed disease. N Engl J Med 379:2131–2139. https://doi.org/10.1056/NEJMoa1714458
doi: 10.1056/NEJMoa1714458
pubmed: 30304647
pmcid: 6481166
Teer JK, Bonnycastle LL, Chines PS, Hansen NF, Aoyama N, Swift AJ, Abaan HO, Albert TJ, Program NCS, Margulies EH, Green ED, Collins FS, Mullikin JC, Biesecker LG (2010) Systematic comparison of three genomic enrichment methods for massively parallel DNA sequencing. Genome Res 20:1420–1431. https://doi.org/10.1101/gr.106716.110
doi: 10.1101/gr.106716.110
pubmed: 20810667
pmcid: 2945191
Umair M, Hayat A (2020) Nonsyndromic split-hand/foot malformation: recent classification. Mol Syndromol 10:243–254. https://doi.org/10.1159/000502784
doi: 10.1159/000502784
pubmed: 32021595
Vasli N, Harris E, Karamchandani J, Bareke E, Majewski J, Romero NB, Stojkovic T, Barresi R, Tasfaout H, Charlton R, Malfatti E, Bohm J, Marini-Bettolo C, Choquet K, Dicaire MJ, Shao YH, Topf A, O’Ferrall E, Eymard B, Straub V, Blanco G, Lochmuller H, Brais B, Laporte J, Tetreault M (2017) Recessive mutations in the kinase ZAK cause a congenital myopathy with fibre type disproportion. Brain 140:37–48. https://doi.org/10.1093/brain/aww257
doi: 10.1093/brain/aww257
pubmed: 27816943
Vind AC, Snieckute G, Blasius M, Tiedje C, Krogh N, Bekker-Jensen DB, Andersen KL, Nordgaard C, Tollenaere MAX, Lund AH, Olsen JV, Nielsen H, Bekker-Jensen S (2020) ZAKalpha recognizes stalled ribosomes through partially redundant sensor domains. Mol Cell 78(700–713):e707. https://doi.org/10.1016/j.molcel.2020.03.021
doi: 10.1016/j.molcel.2020.03.021
Wright JT, Fete M, Schneider H, Zinser M, Koster MI, Clarke AJ, Hadj-Rabia S, Tadini G, Pagnan N, Visinoni AF, Bergendal B, Abbott B, Fete T, Stanford C, Butcher C, D’Souza RN, Sybert VP, Morasso MI (2019) Ectodermal dysplasias: classification and organization by phenotype, genotype and molecular pathway. Am J Med Genet A 179:442–447. https://doi.org/10.1002/ajmg.a.61045
doi: 10.1002/ajmg.a.61045
pubmed: 30703280
Yang Y, Muzny DM, Xia F, Niu Z, Person R, Ding Y, Ward P, Braxton A, Wang M, Buhay C, Veeraraghavan N, Hawes A, Chiang T, Leduc M, Beuten J, Zhang J, He W, Scull J, Willis A, Landsverk M, Craigen WJ, Bekheirnia MR, Stray-Pedersen A, Liu P, Wen S, Alcaraz W, Cui H, Walkiewicz M, Reid J, Bainbridge M, Patel A, Boerwinkle E, Beaudet AL, Lupski JR, Plon SE, Gibbs RA, Eng CM (2014) Molecular findings among patients referred for clinical whole-exome sequencing. JAMA 312:1870–1879. https://doi.org/10.1001/jama.2014.14601
doi: 10.1001/jama.2014.14601
pubmed: 25326635
pmcid: 4326249