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Mutations in human C2CD3 cause skeletal dysplasia and provide new insights into phenotypic and cellular consequences of altered C2CD3 function.

Cortés CR, McInerney-Leo AM, Vogel I, Rondón Galeano MC, Leo PJ, Harris JE, Anderson LK, Keith PA, Brown MA, Ramsing M, Duncan EL, Zankl A, Wicking C - Sci Rep (2016)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Segregation of C2CD3 mutations, and protein ideogram indicating location of variants.(a) C2CD3 variants present in the parents and affected individuals in the reported family. Sequence reads highlight genotype for variants identified by Sanger sequencing under each individual. Arrows denote missense mutation, dotted lines denote deletion site. Note that the sequence scan for the c.195G > C mutation shows the reverse strand sequence; the c.1429delA mutation is shown on the forward strand. (b) Human C2CD3 protein schematic showing mutations detected in the present study (red lines, top), mutations reported in previously reported OFDS cases20 (dotted lines, bottom) and mouse C2cd3 alleles C2Cd3Gt (Gt) and Hearty (Hty) (dotted lines, bottom). Note the C2cd3Gt mutation is predicted to result in a truncated protein encoding the N-terminal 161 amino acids only; aberrant splicing in Hty leads to proteins either truncated at amino acid 235, or with small in-frame deletions in the same region2021. C2: canonical C2 domains, C2CD3N: non-canonical globular C2 domain29.
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f2: Segregation of C2CD3 mutations, and protein ideogram indicating location of variants.(a) C2CD3 variants present in the parents and affected individuals in the reported family. Sequence reads highlight genotype for variants identified by Sanger sequencing under each individual. Arrows denote missense mutation, dotted lines denote deletion site. Note that the sequence scan for the c.195G > C mutation shows the reverse strand sequence; the c.1429delA mutation is shown on the forward strand. (b) Human C2CD3 protein schematic showing mutations detected in the present study (red lines, top), mutations reported in previously reported OFDS cases20 (dotted lines, bottom) and mouse C2cd3 alleles C2Cd3Gt (Gt) and Hearty (Hty) (dotted lines, bottom). Note the C2cd3Gt mutation is predicted to result in a truncated protein encoding the N-terminal 161 amino acids only; aberrant splicing in Hty leads to proteins either truncated at amino acid 235, or with small in-frame deletions in the same region2021. C2: canonical C2 domains, C2CD3N: non-canonical globular C2 domain29.

Mentions: DNA from individual G3P1 was subject to whole exome sequencing. After filtering for quality control, seven genes (FAM160B1, FCF1, OVGP1, TTN, KIA1109, PDK4, and C2CD3) contained two or more variants that were either novel or rare (minor allele frequency <0.005) and of potential functional consequence, thus fitting compound heterozygous inheritance (See Table 1). Using the same parameters, two genes contained homozygous variants (FRMPD2 and PTGFRN), but this pattern of inheritance was considered less likely in a non-consanguineous family with a rare disease. Of the genes identified, only C2CD3 was known to be involved in ciliogenesis, with mutations known to cause a ciliopathy phenotype in both humans and animal models20212324. We did not detect any single heterozygous good quality rare (MAF < 0.005) coding/splice site variant in any other known ciliopathy or OFD gene; thus it is unlikely compound heterozygous mutations in another ciliopathy gene were missed through poor coverage. Sanger sequencing confirmed appropriate segregation of the C2CD3 variants in the parents and affected individuals in this family (Fig. 2a).


Mutations in human C2CD3 cause skeletal dysplasia and provide new insights into phenotypic and cellular consequences of altered C2CD3 function.

Cortés CR, McInerney-Leo AM, Vogel I, Rondón Galeano MC, Leo PJ, Harris JE, Anderson LK, Keith PA, Brown MA, Ramsing M, Duncan EL, Zankl A, Wicking C - Sci Rep (2016)

Segregation of C2CD3 mutations, and protein ideogram indicating location of variants.(a) C2CD3 variants present in the parents and affected individuals in the reported family. Sequence reads highlight genotype for variants identified by Sanger sequencing under each individual. Arrows denote missense mutation, dotted lines denote deletion site. Note that the sequence scan for the c.195G > C mutation shows the reverse strand sequence; the c.1429delA mutation is shown on the forward strand. (b) Human C2CD3 protein schematic showing mutations detected in the present study (red lines, top), mutations reported in previously reported OFDS cases20 (dotted lines, bottom) and mouse C2cd3 alleles C2Cd3Gt (Gt) and Hearty (Hty) (dotted lines, bottom). Note the C2cd3Gt mutation is predicted to result in a truncated protein encoding the N-terminal 161 amino acids only; aberrant splicing in Hty leads to proteins either truncated at amino acid 235, or with small in-frame deletions in the same region2021. C2: canonical C2 domains, C2CD3N: non-canonical globular C2 domain29.
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Related In: Results  -  Collection

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f2: Segregation of C2CD3 mutations, and protein ideogram indicating location of variants.(a) C2CD3 variants present in the parents and affected individuals in the reported family. Sequence reads highlight genotype for variants identified by Sanger sequencing under each individual. Arrows denote missense mutation, dotted lines denote deletion site. Note that the sequence scan for the c.195G > C mutation shows the reverse strand sequence; the c.1429delA mutation is shown on the forward strand. (b) Human C2CD3 protein schematic showing mutations detected in the present study (red lines, top), mutations reported in previously reported OFDS cases20 (dotted lines, bottom) and mouse C2cd3 alleles C2Cd3Gt (Gt) and Hearty (Hty) (dotted lines, bottom). Note the C2cd3Gt mutation is predicted to result in a truncated protein encoding the N-terminal 161 amino acids only; aberrant splicing in Hty leads to proteins either truncated at amino acid 235, or with small in-frame deletions in the same region2021. C2: canonical C2 domains, C2CD3N: non-canonical globular C2 domain29.
Mentions: DNA from individual G3P1 was subject to whole exome sequencing. After filtering for quality control, seven genes (FAM160B1, FCF1, OVGP1, TTN, KIA1109, PDK4, and C2CD3) contained two or more variants that were either novel or rare (minor allele frequency <0.005) and of potential functional consequence, thus fitting compound heterozygous inheritance (See Table 1). Using the same parameters, two genes contained homozygous variants (FRMPD2 and PTGFRN), but this pattern of inheritance was considered less likely in a non-consanguineous family with a rare disease. Of the genes identified, only C2CD3 was known to be involved in ciliogenesis, with mutations known to cause a ciliopathy phenotype in both humans and animal models20212324. We did not detect any single heterozygous good quality rare (MAF < 0.005) coding/splice site variant in any other known ciliopathy or OFD gene; thus it is unlikely compound heterozygous mutations in another ciliopathy gene were missed through poor coverage. Sanger sequencing confirmed appropriate segregation of the C2CD3 variants in the parents and affected individuals in this family (Fig. 2a).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus