Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy

Carol Anne Martin; Ilyas Ahmad; Anna Klingseisen; Muhammad Sajid Hussain; Louise S. Bicknell; Andrea Leitch; Gudrun Nürnberg; Mohammad Reza Toliat; Jennie E. Murray; David Hunt; Fawad Khan; Zafar Ali; Sigrid Tinschert; James Ding; Charlotte Keith; Margaret E. Harley; Patricia Heyn; Rolf Müller; Ingrid Hoffmann; Valérie Cormier Daire; Hélène Dollfus; Lucie Dupuis; Anu Bashamboo; Kenneth McElreavey; Ariana Kariminejad; Roberto Mendoza-Londono; Anthony T. Moore; Anand Saggar; Catie Schlechter; Richard Weleber; Holger Thiele; Janine Altmüller; Wolfgang Höhne; Matthew E. Hurles; Angelika Anna Noegel; Shahid Mahmood Baig; Peter Nürnberg; Andrew P. Jackson

doi:10.1038/ng.3122

Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy

Carol Anne Martin, Ilyas Ahmad (Shared First Author), Anna Klingseisen, Muhammad Sajid Hussain, Louise S. Bicknell, Andrea Leitch, Gudrun Nürnberg, Mohammad Reza Toliat, Jennie E. Murray, David Hunt, Fawad Khan, Zafar Ali, Sigrid Tinschert, James Ding, Charlotte Keith, Margaret E. Harley, Patricia Heyn, Rolf Müller, Ingrid Hoffmann, Valérie Cormier DaireHélène Dollfus, Lucie Dupuis, Anu Bashamboo, Kenneth McElreavey, Ariana Kariminejad, Roberto Mendoza-Londono, Anthony T. Moore, Anand Saggar, Catie Schlechter, Richard Weleber, Holger Thiele, Janine Altmüller, Wolfgang Höhne, Matthew E. Hurles, Angelika Anna Noegel, Shahid Mahmood Baig, Peter Nürnberg, Andrew P. Jackson^*

^*Corresponding author for this work

Clinic of Internal Medicine II - Cardiology

153 Citations (Scopus)

Abstract

Centrioles are essential for ciliogenesis. However, mutations in centriole biogenesis genes have been reported in primary microcephaly and Seckel syndrome, disorders without the hallmark clinical features of ciliopathies. Here we identify mutations in the genes encoding PLK4 kinase, a master regulator of centriole duplication, and its substrate TUBGCP6 in individuals with microcephalic primordial dwarfism and additional congenital anomalies, including retinopathy, thereby extending the human phenotypic spectrum associated with centriole dysfunction. Furthermore, we establish that different levels of impaired PLK4 activity result in growth and cilia phenotypes, providing a mechanism by which microcephaly disorders can occur with or without ciliopathic features.

Original language	English
Journal	Nature Genetics
Volume	46
Issue number	12
Pages (from-to)	1283-1292
Number of pages	10
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.3122
Publication status	Published - 11.12.2014

Funding

We thank the families and clinicians for their involvement and participation; P. Mills, T. Hurd, M. Bettencourt-Dias and M. Reijns for commenting on the manuscript; N. Hastie, D. Fitzpatrick and J. Livingston for helpful discussions; C. Janke (Institut Curie) for his kind gift of the GT335 antibody; E. Freyer for assistance with FACS analysis; P. Gautier for bioinformatics; P. Carroll and A. Vickers for technical assistance; the IGMM core sequencing service; the IGMM imaging facility for assistance with microscopy; E. Patton and the IGMM fish facility for advice and zebrafish technical assistance; E. Liston and the DNA Resource Centre at SickKids for sample processing; A. Pearce and E. Maher (Cytogenetics Laboratory, South East Scotland Genetics Service) for technical advice; G. Hahn (University Hospital Carl Gustav Carus) for her second opinion on the MRI data; and N. Dalibor and E. Kirst (CCG) for their expert technical assistance. This work was supported by funding from the MRC, the Lister Institute for Preventative Medicine and the European Research Council (ERC, 281847) (A.P.J.), Medical Research Scotland (L.S.B.), the National Institute for Health Research Moorfields Eye Hospital Biomedical Research Centre (A.T.M.), Köln Fortune (M.S.H.) and CMMC (P.N. and A.A.N.).

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Martin, C. A., Ahmad, I., Klingseisen, A., Hussain, M. S., Bicknell, L. S., Leitch, A., Nürnberg, G., Toliat, M. R., Murray, J. E., Hunt, D., Khan, F., Ali, Z., Tinschert, S., Ding, J., Keith, C., Harley, M. E., Heyn, P., Müller, R., Hoffmann, I., ... Jackson, A. P. (2014). Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy. Nature Genetics, 46(12), 1283-1292. https://doi.org/10.1038/ng.3122

@article{41ff88bd4ab448528fe4881cfc1052ee,

title = "Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy",

abstract = "Centrioles are essential for ciliogenesis. However, mutations in centriole biogenesis genes have been reported in primary microcephaly and Seckel syndrome, disorders without the hallmark clinical features of ciliopathies. Here we identify mutations in the genes encoding PLK4 kinase, a master regulator of centriole duplication, and its substrate TUBGCP6 in individuals with microcephalic primordial dwarfism and additional congenital anomalies, including retinopathy, thereby extending the human phenotypic spectrum associated with centriole dysfunction. Furthermore, we establish that different levels of impaired PLK4 activity result in growth and cilia phenotypes, providing a mechanism by which microcephaly disorders can occur with or without ciliopathic features.",

author = "Martin, \{Carol Anne\} and Ilyas Ahmad and Anna Klingseisen and Hussain, \{Muhammad Sajid\} and Bicknell, \{Louise S.\} and Andrea Leitch and Gudrun N{\"u}rnberg and Toliat, \{Mohammad Reza\} and Murray, \{Jennie E.\} and David Hunt and Fawad Khan and Zafar Ali and Sigrid Tinschert and James Ding and Charlotte Keith and Harley, \{Margaret E.\} and Patricia Heyn and Rolf M{\"u}ller and Ingrid Hoffmann and Daire, \{Val{\'e}rie Cormier\} and H{\'e}l{\`e}ne Dollfus and Lucie Dupuis and Anu Bashamboo and Kenneth McElreavey and Ariana Kariminejad and Roberto Mendoza-Londono and Moore, \{Anthony T.\} and Anand Saggar and Catie Schlechter and Richard Weleber and Holger Thiele and Janine Altm{\"u}ller and Wolfgang H{\"o}hne and Hurles, \{Matthew E.\} and Noegel, \{Angelika Anna\} and Baig, \{Shahid Mahmood\} and Peter N{\"u}rnberg and Jackson, \{Andrew P.\}",

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doi = "10.1038/ng.3122",

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Martin, CA, Ahmad, I, Klingseisen, A, Hussain, MS, Bicknell, LS, Leitch, A, Nürnberg, G, Toliat, MR, Murray, JE, Hunt, D, Khan, F, Ali, Z, Tinschert, S, Ding, J, Keith, C, Harley, ME, Heyn, P, Müller, R, Hoffmann, I, Daire, VC, Dollfus, H, Dupuis, L, Bashamboo, A, McElreavey, K, Kariminejad, A, Mendoza-Londono, R, Moore, AT, Saggar, A, Schlechter, C, Weleber, R, Thiele, H, Altmüller, J, Höhne, W, Hurles, ME, Noegel, AA, Baig, SM, Nürnberg, P & Jackson, AP 2014, 'Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy', Nature Genetics, vol. 46, no. 12, pp. 1283-1292. https://doi.org/10.1038/ng.3122

TY - JOUR

T1 - Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy

AU - Martin, Carol Anne

AU - Klingseisen, Anna

AU - Hussain, Muhammad Sajid

AU - Bicknell, Louise S.

AU - Leitch, Andrea

AU - Nürnberg, Gudrun

AU - Toliat, Mohammad Reza

AU - Murray, Jennie E.

AU - Hunt, David

AU - Khan, Fawad

AU - Ali, Zafar

AU - Tinschert, Sigrid

AU - Ding, James

AU - Keith, Charlotte

AU - Harley, Margaret E.

AU - Heyn, Patricia

AU - Müller, Rolf

AU - Hoffmann, Ingrid

AU - Daire, Valérie Cormier

AU - Dollfus, Hélène

AU - Dupuis, Lucie

AU - Bashamboo, Anu

AU - McElreavey, Kenneth

AU - Kariminejad, Ariana

AU - Mendoza-Londono, Roberto

AU - Moore, Anthony T.

AU - Saggar, Anand

AU - Schlechter, Catie

AU - Weleber, Richard

AU - Thiele, Holger

AU - Altmüller, Janine

AU - Höhne, Wolfgang

AU - Hurles, Matthew E.

AU - Noegel, Angelika Anna

AU - Baig, Shahid Mahmood

AU - Nürnberg, Peter

AU - Jackson, Andrew P.

A2 - Ahmad, Ilyas

PY - 2014/12/11

Y1 - 2014/12/11

N2 - Centrioles are essential for ciliogenesis. However, mutations in centriole biogenesis genes have been reported in primary microcephaly and Seckel syndrome, disorders without the hallmark clinical features of ciliopathies. Here we identify mutations in the genes encoding PLK4 kinase, a master regulator of centriole duplication, and its substrate TUBGCP6 in individuals with microcephalic primordial dwarfism and additional congenital anomalies, including retinopathy, thereby extending the human phenotypic spectrum associated with centriole dysfunction. Furthermore, we establish that different levels of impaired PLK4 activity result in growth and cilia phenotypes, providing a mechanism by which microcephaly disorders can occur with or without ciliopathic features.

AB - Centrioles are essential for ciliogenesis. However, mutations in centriole biogenesis genes have been reported in primary microcephaly and Seckel syndrome, disorders without the hallmark clinical features of ciliopathies. Here we identify mutations in the genes encoding PLK4 kinase, a master regulator of centriole duplication, and its substrate TUBGCP6 in individuals with microcephalic primordial dwarfism and additional congenital anomalies, including retinopathy, thereby extending the human phenotypic spectrum associated with centriole dysfunction. Furthermore, we establish that different levels of impaired PLK4 activity result in growth and cilia phenotypes, providing a mechanism by which microcephaly disorders can occur with or without ciliopathic features.

UR - https://www.scopus.com/pages/publications/84927581261

U2 - 10.1038/ng.3122

DO - 10.1038/ng.3122

M3 - Journal articles

C2 - 25344692

AN - SCOPUS:84927581261

SN - 1061-4036

VL - 46

SP - 1283

EP - 1292

JO - Nature Genetics

JF - Nature Genetics

IS - 12

ER -

Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy

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