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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

Clinical features of the two subjects in this study.(a–g) G2P1; (h–k) G3P1. Common features include short ribs, shortened long bones, micrognathia (arrow, b,e,i) and trident acetubula (arrow, a,h). G2P1 displayed preaxial polydactyly (duplicated hallux) of the feet (arrow, c,g), and no polydactyly of the hands, although digits appear short (d,f). G3P1 displayed preaxial polydactyly (triplicated hallux) of the feet (arrow j), and pre- (arrow, k) and postaxial (arrowhead, k) polydactyly of the hands. The tibiae in G3P1 were hypoplastic (arrowhead, h) but appeared normal in G2P1.
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f1: Clinical features of the two subjects in this study.(a–g) G2P1; (h–k) G3P1. Common features include short ribs, shortened long bones, micrognathia (arrow, b,e,i) and trident acetubula (arrow, a,h). G2P1 displayed preaxial polydactyly (duplicated hallux) of the feet (arrow, c,g), and no polydactyly of the hands, although digits appear short (d,f). G3P1 displayed preaxial polydactyly (triplicated hallux) of the feet (arrow j), and pre- (arrow, k) and postaxial (arrowhead, k) polydactyly of the hands. The tibiae in G3P1 were hypoplastic (arrowhead, h) but appeared normal in G2P1.

Mentions: We identified a non-consanguineous family from Lebanon of Palestinian descent, with two consecutive pregnancies complicated by skeletal dysplasia. The first and fourth pregnancies resulted in healthy children. Prenatal ultrasound examination at 20 + 3 weeks of the first affected fetus (G2P1) showed normal biparietal diameter but short tubular bones, polydactyly, renal cysts and Dandy-Walker malformation. The pregnancy was terminated, and subsequent autopsy revealed a female fetus with facial dysmorphism (microphthalmia, hypertelorism, flat and broad nasal bridge, dysplastic and posteriorly rotated ears, micrognathia, and a high arched palate), preaxial polydactyly of the feet presenting as a duplicated and bent hallux, brachydactyly, short ribs, short bent tubular bones, trident acetabula (Fig. 1a–g) and a number of ductal kidney cysts. The anus was anteriorly located, and atypical lung lobation, symmetrical liver, and mobile caecum were observed. The brain was not examined at post-mortem in accordance with parental wishes. In a subsequent pregnancy, an early ultrasound scan at 15 + 2 weeks revealed a male fetus (G3P1) with short and bent tubular bones. Autopsy following termination of pregnancy revealed facial dysmorphism, preaxial polydactyly of the hands and feet (presenting as duplication of the thumb and triplication of the hallux), postaxial polydactyly of the hands, hypoplastic tibia, short ribs, short bent tubular bones, trident acetabula (Fig. 1h–k) and kidney cysts. Unlike G2P1, a minor heart malformation (atrial septal defect) was also detected in G3P1. Lungs were without lobation, liver was symmetrical and caecum was mobile. Micropenis/ambiguous genitalia were also noted. Permission was given for cerebrum autopsy, revealing holoprosencephaly, Dandy-Walker malformation with a dilated cisterna magnum and vermis aplasia, cerebellar hypoplasia, polymicrogyria, and hydrocephalus (not shown). A clinical diagnosis of a skeletal ciliopathy was made, but due to the clinical overlap between various forms of OFDS, SRPS and JATD, a more specific diagnosis could not be established.


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)

Clinical features of the two subjects in this study.(a–g) G2P1; (h–k) G3P1. Common features include short ribs, shortened long bones, micrognathia (arrow, b,e,i) and trident acetubula (arrow, a,h). G2P1 displayed preaxial polydactyly (duplicated hallux) of the feet (arrow, c,g), and no polydactyly of the hands, although digits appear short (d,f). G3P1 displayed preaxial polydactyly (triplicated hallux) of the feet (arrow j), and pre- (arrow, k) and postaxial (arrowhead, k) polydactyly of the hands. The tibiae in G3P1 were hypoplastic (arrowhead, h) but appeared normal in G2P1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4837335&req=5

f1: Clinical features of the two subjects in this study.(a–g) G2P1; (h–k) G3P1. Common features include short ribs, shortened long bones, micrognathia (arrow, b,e,i) and trident acetubula (arrow, a,h). G2P1 displayed preaxial polydactyly (duplicated hallux) of the feet (arrow, c,g), and no polydactyly of the hands, although digits appear short (d,f). G3P1 displayed preaxial polydactyly (triplicated hallux) of the feet (arrow j), and pre- (arrow, k) and postaxial (arrowhead, k) polydactyly of the hands. The tibiae in G3P1 were hypoplastic (arrowhead, h) but appeared normal in G2P1.
Mentions: We identified a non-consanguineous family from Lebanon of Palestinian descent, with two consecutive pregnancies complicated by skeletal dysplasia. The first and fourth pregnancies resulted in healthy children. Prenatal ultrasound examination at 20 + 3 weeks of the first affected fetus (G2P1) showed normal biparietal diameter but short tubular bones, polydactyly, renal cysts and Dandy-Walker malformation. The pregnancy was terminated, and subsequent autopsy revealed a female fetus with facial dysmorphism (microphthalmia, hypertelorism, flat and broad nasal bridge, dysplastic and posteriorly rotated ears, micrognathia, and a high arched palate), preaxial polydactyly of the feet presenting as a duplicated and bent hallux, brachydactyly, short ribs, short bent tubular bones, trident acetabula (Fig. 1a–g) and a number of ductal kidney cysts. The anus was anteriorly located, and atypical lung lobation, symmetrical liver, and mobile caecum were observed. The brain was not examined at post-mortem in accordance with parental wishes. In a subsequent pregnancy, an early ultrasound scan at 15 + 2 weeks revealed a male fetus (G3P1) with short and bent tubular bones. Autopsy following termination of pregnancy revealed facial dysmorphism, preaxial polydactyly of the hands and feet (presenting as duplication of the thumb and triplication of the hallux), postaxial polydactyly of the hands, hypoplastic tibia, short ribs, short bent tubular bones, trident acetabula (Fig. 1h–k) and kidney cysts. Unlike G2P1, a minor heart malformation (atrial septal defect) was also detected in G3P1. Lungs were without lobation, liver was symmetrical and caecum was mobile. Micropenis/ambiguous genitalia were also noted. Permission was given for cerebrum autopsy, revealing holoprosencephaly, Dandy-Walker malformation with a dilated cisterna magnum and vermis aplasia, cerebellar hypoplasia, polymicrogyria, and hydrocephalus (not shown). A clinical diagnosis of a skeletal ciliopathy was made, but due to the clinical overlap between various forms of OFDS, SRPS and JATD, a more specific diagnosis could not be established.

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