Mutations in human C2CD3 cause skeletal dysplasia and provide new insights into phenotypic and cellular consequences of altered C2CD3 function.
Ciliopathies are a group of genetic disorders caused by defective assembly or dysfunction of the primary cilium, a microtubule-based cellular organelle that plays a key role in developmental signalling. Ciliopathies are clinically grouped in a large number of overlapping disorders, including the orofaciodigital syndromes (OFDS), the short rib polydactyly syndromes and Jeune asphyxiating thoracic dystrophy. Recently, mutations in the gene encoding the centriolar protein C2CD3 have been described in two families with a new sub-type of OFDS (OFD14), with microcephaly and cerebral malformations. Here we describe a third family with novel compound heterozygous C2CD3 mutations in two fetuses with a different clinical presentation, dominated by skeletal dysplasia with no microcephaly. Analysis of fibroblast cultures derived from one of these fetuses revealed a reduced ability to form cilia, consistent with previous studies in C2cd3-mutant mouse and chicken cells. More detailed analyses support a role for C2CD3 in basal body maturation; but in contrast to previous mouse studies the normal recruitment of the distal appendage protein CEP164 suggests that this protein is not sufficient for efficient basal body maturation and subsequent axonemal extension in a C2CD3-defective background.
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Claudio R
CR
Cortés
The University of Queensland Diamantina Institute, University of Queensland, Australia.
Aideen M
AM
McInerney-Leo
Department of Clinical Genetics, Aarhus University Hospital, Denmark.
Ida
I
Vogel
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Maria C
MC
Rondón Galeano
The University of Queensland Diamantina Institute, University of Queensland, Australia.
Paul J
PJ
Leo
The University of Queensland Diamantina Institute, University of Queensland, Australia.
Jessica E
JE
Harris
The University of Queensland Diamantina Institute, University of Queensland, Australia.
Lisa K
LK
Anderson
The University of Queensland Diamantina Institute, University of Queensland, Australia.
Patricia A
PA
Keith
Queensland University of Technology (QUT), Institute of Health and Biomedical Innovation (IHBI), Queensland, Australia.
Matthew A
MA
Brown
Department of Pathology, Aarhus University Hospital, Denmark.
Mette
M
Ramsing
The University of Queensland Diamantina Institute, University of Queensland, Australia.|Queensland University of Technology (QUT), Institute of Health and Biomedical Innovation (IHBI), Queensland, Australia.|Department of Endocrinology, James Mayne Building, Royal Brisbane and Women's Hospital, Butterfield Road, Herston, QLD 4029, Australia.
Emma L
EL
Duncan
Academic Department of Medical Genetics, Sydney Children's Hospitals Network (Westmead), Westmead, NSW 2145, Australia.|Childrens Hospital Westmead Clinical School, Sydney Medical School, The University of Sydney, NSW 2145, Australia.|Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.
Andreas
A
Zankl
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Carol
C
Wicking
D000818:Animals; D002923:Cilia / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D005190:Family; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D010009:Osteochondrodysplasias / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D010375:Pedigree; D010641:Phenotype; D011859:Radiography
C000594350:C2cd3 protein, human; D008869:Microtubule-Associated Proteins