SHP2's gain-of-function in Werner syndrome causes childhood disease onset likely resulting from negative genetic interaction.
MAPK
Noonan syndrome
PTPN11
SHP2
WRN
Werner syndrome
genetic interaction
replicative senescence
Journal
Clinical genetics
ISSN: 1399-0004
Titre abrégé: Clin Genet
Pays: Denmark
ID NLM: 0253664
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
revised:
21
03
2022
received:
17
02
2022
accepted:
05
04
2022
pubmed:
10
4
2022
medline:
16
6
2022
entrez:
9
4
2022
Statut:
ppublish
Résumé
Prompt diagnosis of complex phenotypes is a challenging task in clinical genetics. Whole exome sequencing has proved to be effective in solving such conditions. Here, we report on an unpredictable presentation of Werner Syndrome (WRNS) in a 12-year-old girl carrying a homozygous truncating variant in RECQL2, the gene mutated in WRNS, and a de novo activating missense change in PTPN11, the major Noonan syndrome gene, encoding SHP2, a protein tyrosine phosphatase positively controlling RAS function and MAPK signaling, which have tightly been associated with senescence in primary cells. All the major WRNS clinical criteria were present with an extreme precocious onset and were associated with mild intellectual disability, severe growth retardation and facial dysmorphism. Compared to primary fibroblasts from adult subjects with WRNS, proband's fibroblasts showed a dramatically reduced proliferation rate and competence, and a more accelerated senescence, in line with the anticipated WRNS features occurring in the child. In vitro functional characterization of the SHP2 mutant documented its hyperactive behavior and a significantly enhanced activation of the MAPK pathway. Based on the functional interaction of WRN and MAPK signaling in processes relevant to replicative senescence, these findings disclose a unique phenotype likely resulting from negative genetic interaction.
Substances chimiques
Protein Tyrosine Phosphatase, Non-Receptor Type 11
EC 3.1.3.48
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
12-21Informations de copyright
© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Références
Yu CE, Oshima J, Fu YH, et al. Positional cloning of the Werner's syndrome gene. Science. 1996;272:258-262. doi:10.1126/science.272.5259.258
Oshima J, Martin GM, Hisama FM. Werner syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews. University of Washington, Seattle; 2016:1993-2022.
Takemoto M, Mori S, Kuzuya M, et al. Diagnostic criteria for Werner syndrome based on Japanese nationwide epidemiological survey. Geriatr Gerontol Int. 2013;13:475-481. doi:10.1111/j.1447-0594.2012.00913.x
Huang S, Lee L, Hanson NB, et al. The spectrum of WRN mutations in Werner syndrome patients. Hum Mutat. 2006;27:558-567. doi:10.1002/humu.20337
Lauper JM, Krause A, Vaughan TL, Monnat RJ. Spectrum and risk of neoplasia in Werner syndrome: a systematic review. PLoS One. 2013;8:e59709. doi:10.1371/journal.pone.0059709
Yokote K, Chanprassert S, Lee L, et al. WRN mutation update: mutation Spectrum, patient registries, and translational prospects. Hum Mutat. 2017;38:7-15. doi:10.1002/humu.23128
Gray MD, Shen JC, Kamath-Loeb AS, et al. The Werner syndrome protein is a DNA helicase. Nat Genet. 1997;17:100-103. doi:10.1038/ng0997-100
Huang S, Li B, Gray MD, Oshima J, Mian IS, Campisi J. The premature ageing syndrome protein, WRN, is a 3′→5′ exonuclease. Nat Genet. 1998;20:114-116. doi:10.1038/2410
Hu JS, Feng H, Zeng W, Lin GX, Xi XG. Solution structure of a multifunctional DNA- and protein- binding motif of human Werner syndrome protein. Proc Natl Acad Sci U S A. 2005;102:18379-18384. doi:10.1073/pnas.0509380102
Croteau DL, Popuri V, Opresko PL, Bohr VA. Human RecQ helicases in DNA repair, recombination, and replication. Annu Rev Biochem. 2014;83:519-552. doi:10.1146/annurev-biochem-060713-035428
Saintigny Y, Makienko K, Swanson C, Emond MJ, Monnat RJ. Homologous recombination resolution defect in Werner syndrome. Mol Cell Biol. 2002;22:6971-6978. doi:10.1128/MCB.22.20.6971-6978.2002
Crabbe L, Verdun RE, Haggblom CI, Karlseder J. Defective telomere lagging strand synthesis in cells lacking WRN helicase activity. Science. 2004;306:1951-1953. doi:10.1126/science.1103619
Pichierri P, Franchitto A, Mosesso P, Palitti F. Werner's syndrome protein is required for correct recovery after replication arrest and DNA damage induced in S-phase of cell cycle. Mol Biol Cell. 2001;12:2412-2421. doi:10.1091/mbc.12.8.2412
Poot M, Gollahon KA, Emond MJ, Silber JR, Rabinovitch PS. Werner syndrome diploid fibroblasts are sensitive to 4-nitroquinoline-N-oxide and 8-methoxypsoralen: implications for the disease phenotype. Faseb J. 2002;16:757-758. doi:10.1096/fj.01-0906fje
Mukherjee S, Sinha D, Bhattacharya S, Srinivasan K, Abdisalaam S, Asaithamby A. Werner syndrome protein and DNA replication. Int J Mol Sci. 2018;19:3442-3460. doi:10.3390/ijms19113442
Roberts AE. Noonan Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews. University of Washington, Seattle; 2022 1993-2022.
van der Burgt I. Noonan syndrome. Orphanet J Rare Dis. 2007;14:2-4. doi:10.1186/1750-1172-2-4
Tartaglia M, Gelb BD, Zenker M. Noonan syndrome and clinically related disorders. Best Pract Res Clin Endocrinol Metab. 2011;25:161-179. doi:10.1016/j.beem.2010.09.002
Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lancet. 2013;381:333-342. doi:10.1016/S0140-6736(12)61023-X
Tartaglia M, Mehler EL, Goldberg R, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001;29:465-468. doi:10.1038/ng772
Tartaglia M, Niemeyer CM, Shannon KM, Loh ML. SHP-2 and myeloid malignancies. Curr Opin Hematol. 2004;11:44-50. doi:10.1097/00062752-200401000-00007
Cagnol S, Chambard JC. ERK and cell death: mechanisms of ERK-induced cell death-apoptosis, autophagy and senescence. FEBS J. 2010;277:2-21. doi:10.1111/j.1742-4658.2009.07366.x
Lindeboom RGH, Vermeulen M, Lehner B, Supek F. The impact of nonsense-mediated mRNA decay on genetic disease, gene editing and cancer immunotherapy. Nat Genet. 2019;51:1645-1651. doi:10.1038/s41588-019-0517-5
Kitano K, Kim S-Y, Hakoshima T. Structural basis for DNA strand separation by the unconventional winged-helix domain of RecQ helicase WRN. Structure. 2010;18:177-187. doi:10.1016/j.str.2009.12.011
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-423. doi:10.1038/gim.2015.30
Fumagalli M, Rossiello F, Mondello C, d'Adda di Fagagna F. Stable cellular senescence is associated with persistent DDR activation. PLoS One. 2014;9:e110969. doi:10.1371/journal.pone.0110969
Pannone L, Bocchinfuso G, Flex E, et al. Structural, functional, and clinical characterization of a novel PTPN11 mutation cluster underlying Noonan syndrome. Hum Mutat. 2017;38:451-459. doi:10.1002/humu.23175B
Ranza E, Guimeier A, Verloes A, et al. Overlapping phenotypes between SHORT and Noonan syndromes in patients with PTPN11 pathogenic variants. Clin Genet. 2020;98:10-18. doi:10.1111/cge.13746
Hennekam RCM. Pathophysiology of premature aging characteristics in Mendelian progeroid disorders. Eur J Med Genet. 2020;63:104028. doi:10.1016/j.ejmg.2020.104028
Matozaki T, Murata Y, Saito Y, Okazawa H, Ohnishi H. Protein tyrosine phosphatase SHP-2: a proto-oncogene product that promotes Ras activation. Cancer Sci. 2009;100:1786-1793. doi:10.1111/j.1349-7006.2009.01257.x
Hof P, Pluskey S, Dhe-Paganon S, Eck MJ, Shoelson SE. Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998;92:441-450. doi:10.1016/s0092-8674(00)80938-1
Tartaglia M, Martinelli S, Stella L, et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006;78:279-290. doi:10.1086/499925
Baryshnikova A, Costanzo M, Myers CL, Andrews B, Boone C. Genetic interaction networks: toward an understanding of heritability. Annu Rev Genomics Hum Genet. 2013;14:111-133. doi:10.1146/annurev-genom-082509-141730
Chan G, Kalaitzidis D, Neel BJ. The tyrosine phosphatase Shp2 (PTPN11) in cancer. Cancer Metas Rev. 2008;27:179-192. doi:10.1007/s10555-008-9126-y35
Rehman AU, Rahman MU, Khan MT, et al. Landscape of protein tyrosine phosphatase (Shp2) and cancer. Curr Pharm Des. 2018;24:3767-3777.
Putlyaeva LV, Demin DE, Uvarova AN, et al. PTPN11 knockdown prevents changes in the expression of genes controlling cell cycle, chemotherapy resistance, and oncogene-induced senescence in human thyroid cells overexpressing BRAF V600E oncogenic protein. Biochemistry (Mosc). 2020;85:108-118. doi:10.1134/S0006297920010101
Liu X, Zheng H, Li X, et al. Gain-of-function mutations of Ptpn11 (Shp2) cause aberrant mitosis and increase susceptibility to DNA damage-induced malignancies. Proc Natl Acad Sci U S A. 2016;113:984-989. doi:10.1073/pnas.1508535113
Li JJ, Kovach AR, De Monia M, et al. Expression of oncogenic HRAS in human Rh28 and RMS-YM rhabdomyosarcoma cells leads to oncogene-induced senescence. Sci Rep. 2021;11:16505. doi:10.1038/s41598-021-95355-2
Santoriello C, Deflorian G, Pezzimenti F, et al. Expression of H-RASV12 in a zebrafish model of Costello syndrome causes cellular senescence in adult proliferating cells. Dis Model Mech. 2009;2:56-67. doi:10.1242/dmm.001016
Smith J, Tho LM, Xu N, Gillespie DA. The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Adv Cancer Res. 2010;108:73-112. doi:10.1016/B978-0-12-380888-2.00003-0
Li Z, Kong Y, Yan S, Ahmad N, Liu X. Plk1 phosphorylation of Mre11 antagonizes the DNA damage response. Cancer Res. 2017;77:3169-3180. doi:10.1158/0008-5472.CAN-16-2787
Rossi ML, Ghosh AK, Bohr VA. Roles of Werner syndrome protein in protection of genome integrity. DNA Repair (Amst). 2010;9:331-344. doi:10.1016/j.dnarep.2009.12.011
Pichierri P, Rosselli F, Franchitto A. Werner's syndrome protein is phosphorylated in an ATR/ATM-dependent manner following replication arrest and DNA damage induced during the S phase of the cell cycle. Oncogene. 2003;22:1491-1500. doi:10.1038/sj.onc.1206169
Ammazzalorso F, Pirzio LM, Bignami M, Franchitto A, Pichierri P. ATR and ATM differently regulate WRN to prevent DSBs at stalled replication forks and promote replication fork recovery. EMBO J. 2010;29:3156-3169. doi:10.1038/emboj.2010.205
Pichierri P, Ammazzalorso F, Bignami M, Franchitto A. The Werner syndrome protein: linking the replication checkpoint response to genome stability. Aging (Albany NY). 2011;3:311-318. doi:10.18632/aging.100293
van Vugt MA, Gardino AK, Linding R, et al. A mitotic phosphorylation feedback network connects Cdk1, Plk1, 53BP1, and Chk2 to inactivate the G(2)/M DNA damage checkpoint. PLoS Biol. 2010;8:e1000287. doi:10.1371/journal.pbio.1000287
Posey JE, Harel T, Liu P, et al. Resolution of disease phenotypes resulting from multilocus genomic variation. N Engl J Med. 2017;376:21-31. doi:10.1056/NEJMoa1516767
Duerinckx S, Jacquemin V, Drunat S, et al. Digenic inheritance of human primary microcephaly delineates centrosomal and non-centrosomal pathways. Hum Mutat. 2020;41:512-524. doi:10.1002/humu.23948
Van Trier DC, van der Burgt I, Draaijer RW, et al. Ocular findings in Noonan syndrome: a retrospective cohort study of 105 patients. Eur J Pediatr. 2018;177:1293-1298. doi:10.1007/s00431-018-3183-1
Donadille B, D'Anella P, Auclair M, et al. Partial lipodystrophy with severe insulin resistance and adult progeria Werner syndrome. Orphanet J Rare Dis. 2013;8:106. doi:10.1186/1750-1172-8-106
Goto M, Ishikawa Y, Sugimoto M, Furuichi Y. Werner syndrome: a changing pattern of clinical manifestations in Japan (1917~2008). Biosci Trends. 2013;7:13-22.