Mutations in the pre-replication complex cause Meier-Gorlin syndrome

Louise S. Bicknell; Ernie M H F Bongers; Andrea Leitch; Stephen Brown; Jeroen Schoots; Margaret E. Harley; Salim Aftimos; Jumana Y. Al-Aama; Michael Bober; Paul A J Brown; Hans Van Bokhoven; John Dean; Alaa Y. Edrees; Murray Feingold; Alan Fryer; Lies H. Hoefsloot; Nikolaus Kau; Nine V A M Knoers; James MacKenzie; John M. Opitz; Pierre Sarda; Alison Ross; I. Karen Temple; Annick Toutain; Carol A. Wise; Michael Wright; Andrew P. Jackson

doi:10.1038/ng.775

Mutations in the pre-replication complex cause Meier-Gorlin syndrome

Louise S. Bicknell, Ernie M H F Bongers, Andrea Leitch, Stephen Brown, Jeroen Schoots, Margaret E. Harley, Salim Aftimos, Jumana Y. Al-Aama, Michael Bober, Paul A J Brown, Hans Van Bokhoven, John Dean, Alaa Y. Edrees, Murray Feingold, Alan Fryer, Lies H. Hoefsloot, Nikolaus Kau, Nine V A M Knoers, James MacKenzie, John M. OpitzPierre Sarda, Alison Ross, I. Karen Temple, Annick Toutain, Carol A. Wise, Michael Wright, Andrew P. Jackson

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196 Scopus citations

Abstract

Meier-Gorlin syndrome (ear, patella and short-stature syndrome) is an autosomal recessive primordial dwarfism syndrome characterized by absent or hypoplastic patellae and markedly small ears. Both pre- and post-natal growth are impaired in this disorder, and although microcephaly is often evident, intellect is usually normal in this syndrome. We report here that individuals with this disorder show marked locus heterogeneity, and we identify mutations in five separate genes: ORC1, ORC4, ORC6, CDT1 and CDC6. All of these genes encode components of the pre-replication complex, implicating defects in replication licensing as the cause of a genetic syndrome with distinct developmental abnormalities.

Original language	English (US)
Pages (from-to)	356-360
Number of pages	5
Journal	Nature genetics
Volume	43
Issue number	4
DOIs	https://doi.org/10.1038/ng.775
State	Published - Feb 2011

ASJC Scopus subject areas

Genetics

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Bicknell, L. S., Bongers, E. M. H. F., Leitch, A., Brown, S., Schoots, J., Harley, M. E., Aftimos, S., Al-Aama, J. Y., Bober, M., Brown, P. A. J., Van Bokhoven, H., Dean, J., Edrees, A. Y., Feingold, M., Fryer, A., Hoefsloot, L. H., Kau, N., Knoers, N. V. A. M., MacKenzie, J., ... Jackson, A. P. (2011). Mutations in the pre-replication complex cause Meier-Gorlin syndrome. Nature genetics, 43(4), 356-360. https://doi.org/10.1038/ng.775

Bicknell, LS, Bongers, EMHF, Leitch, A, Brown, S, Schoots, J, Harley, ME, Aftimos, S, Al-Aama, JY, Bober, M, Brown, PAJ, Van Bokhoven, H, Dean, J, Edrees, AY, Feingold, M, Fryer, A, Hoefsloot, LH, Kau, N, Knoers, NVAM, MacKenzie, J, Opitz, JM, Sarda, P, Ross, A, Temple, IK, Toutain, A, Wise, CA, Wright, M & Jackson, AP 2011, 'Mutations in the pre-replication complex cause Meier-Gorlin syndrome', Nature genetics, vol. 43, no. 4, pp. 356-360. https://doi.org/10.1038/ng.775

@article{c57503c3265c41e2a6d0e2bc1a31b77b,

title = "Mutations in the pre-replication complex cause Meier-Gorlin syndrome",

abstract = "Meier-Gorlin syndrome (ear, patella and short-stature syndrome) is an autosomal recessive primordial dwarfism syndrome characterized by absent or hypoplastic patellae and markedly small ears. Both pre- and post-natal growth are impaired in this disorder, and although microcephaly is often evident, intellect is usually normal in this syndrome. We report here that individuals with this disorder show marked locus heterogeneity, and we identify mutations in five separate genes: ORC1, ORC4, ORC6, CDT1 and CDC6. All of these genes encode components of the pre-replication complex, implicating defects in replication licensing as the cause of a genetic syndrome with distinct developmental abnormalities.",

author = "Bicknell, {Louise S.} and Bongers, {Ernie M H F} and Andrea Leitch and Stephen Brown and Jeroen Schoots and Harley, {Margaret E.} and Salim Aftimos and Al-Aama, {Jumana Y.} and Michael Bober and Brown, {Paul A J} and {Van Bokhoven}, Hans and John Dean and Edrees, {Alaa Y.} and Murray Feingold and Alan Fryer and Hoefsloot, {Lies H.} and Nikolaus Kau and Knoers, {Nine V A M} and James MacKenzie and Opitz, {John M.} and Pierre Sarda and Alison Ross and Temple, {I. Karen} and Annick Toutain and Wise, {Carol A.} and Michael Wright and Jackson, {Andrew P.}",

note = "Funding Information: We thank the subjects and their families for participation in this study and all clinicians for contributing samples not included in this manuscript. Also the late Robert J. Gorlin for contributing individual P3 to the study; E.S. Gray for pathology; M. Ansari, S. McKay, S.D. van der VeldeVisser, T.H. Merkx, S. Devroy and the MRC HGU core sequencing service for advice and technical support; E. Maher and colleagues for cytogenetic advice and assistance; and V. van Heyningen, N. Hastie, D. Fitzpatrick, I. Jackson and J. Blow for discussions and comments. This work was supported by funding from the MRC and Lister Institute of Preventative Medicine. A.P.J. is an MRC Senior Clinical Fellow and Lister Institute Prize fellow.",

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doi = "10.1038/ng.775",

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AU - Bongers, Ernie M H F

AU - Leitch, Andrea

AU - Brown, Stephen

AU - Schoots, Jeroen

AU - Harley, Margaret E.

AU - Aftimos, Salim

AU - Al-Aama, Jumana Y.

AU - Bober, Michael

AU - Brown, Paul A J

AU - Van Bokhoven, Hans

AU - Dean, John

AU - Edrees, Alaa Y.

AU - Feingold, Murray

AU - Fryer, Alan

AU - Hoefsloot, Lies H.

AU - Kau, Nikolaus

AU - Knoers, Nine V A M

AU - MacKenzie, James

AU - Opitz, John M.

AU - Sarda, Pierre

AU - Ross, Alison

AU - Temple, I. Karen

AU - Toutain, Annick

AU - Wise, Carol A.

AU - Wright, Michael

AU - Jackson, Andrew P.

N1 - Funding Information: We thank the subjects and their families for participation in this study and all clinicians for contributing samples not included in this manuscript. Also the late Robert J. Gorlin for contributing individual P3 to the study; E.S. Gray for pathology; M. Ansari, S. McKay, S.D. van der VeldeVisser, T.H. Merkx, S. Devroy and the MRC HGU core sequencing service for advice and technical support; E. Maher and colleagues for cytogenetic advice and assistance; and V. van Heyningen, N. Hastie, D. Fitzpatrick, I. Jackson and J. Blow for discussions and comments. This work was supported by funding from the MRC and Lister Institute of Preventative Medicine. A.P.J. is an MRC Senior Clinical Fellow and Lister Institute Prize fellow.

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Mutations in the pre-replication complex cause Meier-Gorlin syndrome

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