Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes
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Citações na Scopus
23
Tipo de produção
article
Data de publicação
2019
Editora
CELL PRESS
Indexadores
Título da Revista
ISSN da Revista
Título do Volume
Autores
BURRAGE, Lindsay C.
REYNOLDS, John J.
BARATANG, Nissan Vida
PHILLIPS, Jennifer B.
WEGNER, Jeremy
MCFARQUHAR, Ashley
HIGGS, Martin R.
CHRISTIANSEN, Audrey E.
LANZA, Denise G.
SEAVITT, John R.
Autor de Grupo de pesquisa
Univ Washington Ctr Mendelian
Undiagnosed Dis Network
Editores
Coordenadores
Organizadores
Citação
AMERICAN JOURNAL OF HUMAN GENETICS, v.104, n.3, p.422-438, 2019
Resumo
SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl(-/-) murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl(-/-) zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations.
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Referências
- Adzhubei IA, 2010, NAT METHODS, V7, P248, DOI 10.1038/nmeth0410-248
- Bainbridge MN, 2011, GENOME BIOL, V12, DOI 10.1186/gb-2011-12-7-r68
- Bassett AR, 2013, CELL REP, V4, P220, DOI 10.1016/j.celrep.2013.06.020
- Boerkoel CF, 2002, NAT GENET, V30, P215, DOI 10.1038/ng821
- Campos EI, 2015, MOL CELL, V60, P697, DOI 10.1016/j.molcel.2015.08.005
- Challis D, 2012, BMC BIOINFORMATICS, V13, DOI 10.1186/1471-2105-13-8
- Cooper HA, 2000, AM J MED GENET, V92, P33, DOI 10.1002/(SICI)1096-8628(20000501)92:1<33::AID-AJMG6>3.0.CO;2-U
- Cottineau J, 2017, J CLIN INVEST, V127, P1991, DOI 10.1172/JCI90727
- Desmet FO, 2009, NUCLEIC ACIDS RES, V37, DOI 10.1093/nar/gkp215
- Duro E, 2010, MOL CELL, V40, P632, DOI 10.1016/j.molcel.2010.10.023
- FANCONI S, 1983, HELV PAEDIATR ACTA, V38, P267
- Filocamo M.a, 2014, OPEN J BIORESOURCES
- Gripp KW, 2008, AM J MED GENET A, V146A, P468, DOI 10.1002/ajmg.a.32155
- Halevy RS, 2018, HUM MUTAT, V39, P811, DOI 10.1002/humu.23417
- Harley ME, 2016, NAT GENET, V48, P36, DOI 10.1038/ng.3451
- Hodgkins A, 2015, BIOINFORMATICS, V31, P3078, DOI 10.1093/bioinformatics/btv308
- Huang TH, 2018, MOL CELL, V69, P879, DOI 10.1016/j.molcel.2018.01.031
- Hunter KB, 2010, EUR J PEDIATR, V169, P801, DOI 10.1007/s00431-009-1115-9
- Jian XQ, 2014, NUCLEIC ACIDS RES, V42, P13534, DOI 10.1093/nar/gku1206
- Kircher M, 2014, NAT GENET, V46, P310, DOI 10.1038/ng.2892
- Kumar P, 2009, NAT PROTOC, V4, P1073, DOI 10.1038/nprot.2009.86
- LACHMAN RS, 1989, PEDIATR RADIOL, V19, P417, DOI 10.1007/BF02387640
- Langer LO, 1997, PEDIATR RADIOL, V27, P409, DOI 10.1007/s002470050157
- Langer LO, 1996, AM J MED GENET, V63, P20, DOI 10.1002/(SICI)1096-8628(19960503)63:1<20::AID-AJMG7>3.0.CO;2-W
- Lanza DG, 2018, BMC BIOL, V16, DOI 10.1186/s12915-018-0529-0
- Li H, 2010, BIOINFORMATICS, V26, P589, DOI 10.1093/bioinformatics/btp698
- Li H, 2009, BIOINFORMATICS, V25, P1754, DOI 10.1093/bioinformatics/btp324
- Liu D, 2014, J GENET GENOMICS, V41, P43, DOI 10.1016/j.jgg.2013.11.004
- Lonsdale J, 2013, NAT GENET, V45, P580, DOI 10.1038/ng.2653
- Lopes F, 2018, EUR J NEUROL, V25, pE123, DOI 10.1111/ene.13782
- Masuno M, 1996, AM J MED GENET, V66, P429, DOI 10.1002/(SICI)1096-8628(19961230)66:4<429::AID-AJMG8>3.0.CO;2-F
- McKenna A, 2010, GENOME RES, V20, P1297, DOI 10.1101/gr.107524.110
- Mo DL, 2018, CANCER LETT, V413, P1, DOI 10.1016/j.canlet.2017.10.021
- Morio T, 2017, INT J HEMATOL, V106, P357, DOI 10.1007/s12185-017-2263-8
- Nieminuszczy J, 2016, METHODS, V108, P92, DOI 10.1016/j.ymeth.2016.04.019
- Nishimura G, 1998, AM J MED GENET, V80, P288, DOI 10.1002/(SICI)1096-8628(19981116)80:3<288::AID-AJMG22>3.0.CO;2-A
- O'Connell BC, 2010, MOL CELL, V40, P645, DOI 10.1016/j.molcel.2010.10.022
- O'Donnell L, 2010, MOL CELL, V40, P619, DOI 10.1016/j.molcel.2010.10.024
- Offiah AC, 2001, J MED GENET, V38, P889, DOI 10.1136/jmg.38.12.889
- Piwko W, 2016, EMBO J, V35, P2584, DOI 10.15252/embj.201593132
- Piwko W, 2010, EMBO J, V29, P4210, DOI 10.1038/emboj.2010.304
- Reid JG, 2014, BMC BIOINFORMATICS, V15, DOI 10.1186/1471-2105-15-30
- Renshaw SA, 2006, BLOOD, V108, P3976, DOI 10.1182/blood-2006-05-024075
- Reynolds JJ, 2017, NAT GENET, V49, P537, DOI 10.1038/ng.3790
- Saredi G, 2016, NATURE, V534, P714, DOI 10.1038/nature18312
- Schlacher K, 2011, CELL, V145, P529, DOI 10.1016/j.cell.2011.03.041
- Schwarz JM, 2014, NAT METHODS, V11, P361, DOI 10.1038/nmeth.2890
- Sobreira Nara, 2015, Hum Mutat, V36, P928, DOI 10.1002/humu.22844
- Stewart GS, 1999, CELL, V99, P577, DOI 10.1016/S0092-8674(00)81547-0
- Szafranski P, 2017, MAMM GENOME, V28, P275, DOI 10.1007/s00335-017-9686-7
- Techer H, 2013, J MOL BIOL, V425, P4845, DOI 10.1016/j.jmb.2013.03.040
- Umpaichitra V, 2002, CLIN DYSMORPHOL, V11, P53, DOI 10.1097/00019605-200201000-00011
- Walker MB, 2007, BIOTECH HISTOCHEM, V82, P23, DOI 10.1080/10520290701333558
- Wang AT, 2015, MOL CELL, V59, P478, DOI 10.1016/j.molcel.2015.07.009
- Westerfield M., 2007, ZEBRAFISH BOOK GUIDE
- Yang YP, 2014, JAMA-J AM MED ASSOC, V312, P1870, DOI 10.1001/jama.2014.14601