A novel GJA1 mutation causes oculodentodigital dysplasia without syndactyly

Vitiello, Carmen; D’Adamo, Pio; Gentile, Filomena V; Vingolo, E. M.; Gasparini, Paolo; Banfi, Sandro

doi:10.1002/ajmg.a.30554

Cited by 56 publications

(37 citation statements)

References 10 publications

(20 reference statements)

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“…Currently, twenty-eight different mutations in this gene are known to affect the phenotype (Vitiello et al 2005) by producing abnormal channel proteins that drastically reduce the permeability of various cells including osteoblasts FIGURE 4.-mRNA levels for the marker genes associated with bone development in wild-type (WT) fetuses and heterozygous (HT) and knockout (KO) mutants at different gestational times (dpc ¼ days post coitum) as determined by quantitative real-time polymerase chain reaction (RT-PCR). (A) Alterations in osteocalcin mRNA levels can be observed at 18.5 dpc in HT fetuses and at 18.5 and 19.5 dpc in the KO group.…”

Section: Discussionmentioning

confidence: 99%

Delayed Osteoblastic Differentiation and Bone Development in Cx43 Knockout Mice

et al. 2011

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GJA1 gene (Connexin43, also known as Cx43) is the most abundant gap junction protein isoform in animal cells and is associated with bone development in embryos. The objective of the present work was to evaluate in vivo osteal development in GJA1-deficient fetal mice through determination of the histological and molecular alterations induced by partial or total deletion of the GJA1 gene. Heterozygous C57BL/6 mice (HT) harboring a null mutation of the GJA1 gene were mated, and pregnant females were submitted to euthanasia and Caesarean section from 12.5 to 19.5 days post coitum (dpc). HT (GJA1 þ/-) and homozygous (GJA1 -/-) knockout (KO) mutants and wild-type (WT) fetuses were identified by polymerase chain reaction (PCR), and development curves were constructed on the basis of fetus weight and crown-rump length. Histopathological, histochemical, and realtime PCR analyses were performed in order to assess the expression of markers associated with bone development, namely, osteocalcin, osteopontin, alkaline phosphatase, RUNX2, GJA1, GJC1 (Cx45), and GJA3 (Cx46). HT and KO fetuses exhibited delays in the differentiation of osteoblasts and, consequently, in bone development in comparison with the WT group. Additionally, less deposition of mineralized and osteoid matrix was observed in GJA1-deficient fetuses. Bone development in KO fetuses was delayed through the moment of birth, but in HT animals the delay only extended until 17.5 dpc, following which development was normalized. The expression of genes coding for osteocalcin, osteopontin, alkaline phosphatise, and RUNX2 were also delayed in GJA1-deficient fetuses. Animals that exhibited a lower expression of GJA1 presented delayed expression of the GJC1 and GJA3 genes and their corresponding protein products in the bone tissue. The results of the present study contribute to our understanding of the function of GJA1 during bone development and suggest that GJC1 could play a role in restoring intercellular communication in GJA1-deficient mice.

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Section: Discussionmentioning

confidence: 99%

Delayed Osteoblastic Differentiation and Bone Development in Cx43 Knockout Mice

et al. 2011

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“…Mutations in human GJA1 are predicted to perturb the formation of functional gap junctions. To date, there are 27 reported mutations in the GJA1 gene that are linked to ODDD but, in most cases, the mechanism of action of these mutations remains unclear (Kjaer et al, 2004;Paznekas et al, 2003;Richardson et al, 2004;van Steensel et al, 2005;Vitiello et al, 2005). Recently, it was shown that the G21R and G138R mutations result in loss-of-function Cx43 and these mutants have dominant properties on wild-type Cx43 (Roscoe et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

A Gja1 missense mutation in a mouse model of oculodentodigital dysplasia

et al. 2005

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Oculodentodigital dysplasia (ODDD) is an autosomal dominant disorder characterized by pleiotropic developmental anomalies of the limbs, teeth, face and eyes that was shown recently to be caused by mutations in the gap junction protein alpha 1 gene (GJA1), encoding connexin 43 (Cx43). In the course of performing an Nethyl-N-nitrosourea mutagenesis screen, we identified a dominant mouse mutation that exhibits many classic symptoms of ODDD, including syndactyly, enamel hypoplasia, craniofacial anomalies and cardiac dysfunction. Positional cloning revealed that these mice carry a point mutation in Gja1 leading to the substitution of a highly conserved amino acid (G60S) in Cx43. In vivo and in vitro studies revealed that the mutant Cx43 protein acts in a dominant-negative fashion to disrupt gap junction assembly and function. In addition to the classic features of ODDD, these mutant mice also showed decreased bone mass and mechanical strength, as well as altered hematopoietic stem cell and progenitor populations. Thus, these mice represent an experimental model with which to explore the clinical manifestations of ODDD and to evaluate potential intervention strategies.

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“…23,[26][27][28][29]40,46,47 In the present study, OAG is present in seven of the eight individuals (87.5%) with the GJA1 mutation, which is a significantly higher association than that reported in previous studies.…”

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confidence: 45%

“…Glaucoma has been recorded in 33 of 161 patients with ODDD and GJA1 mutations but in none of the 33 patients with other conditions and GJA1 mutations. 23,[26][27][28][29][30][31]37,40,46,47 These glaucoma-associated mutations distribute randomly in the functional domains of GJA1. It total, glaucoma is reported in~17% of patients (33/194) with GJA1 mutations.…”

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A novel truncation mutation in GJA1 associated with open angle glaucoma and microcornea in a large Chinese family

Huang

Wang

Xiao

et al. 2015

Eye

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Purpose To identify genetic defects in a large family with open angle glaucoma (OAG) and microcornea. Methods Genomic DNA was prepared from leukocytes of 15 individuals from three generations of a Chinese family, including seven individuals with OAG and microcornea, one with microcornea alone, and seven healthy individuals. Whole exome sequencing was performed on genomic DNA of the proband. Candidate variants were obtained through multiple steps of bioinformatics analysis and validated by Sanger sequencing and segregation analysis. Results Exome sequencing detected a candidate variant in GJA1, a novel truncation mutation (c.791_792delAA, p.K264Ifs*43). This mutation was present in all seven individuals with OAG and microcornea and the individual with microcornea alone, but not in the seven unaffected relatives in the family. It was not present in 1394 alleles from 505 unrelated controls without glaucoma and 192 normal controls. Extraocular signs were not observed in seven out of the eight individuals; only one was affected with dental enamel hypoplasia and syndactyly. Conclusions A novel truncation mutation in GJA1 is associated with OAG and microcornea in a Chinese family. This suggests that GJA1 should be included as a candidate gene for glaucoma.

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A novel GJA1 mutation causes oculodentodigital dysplasia without syndactyly

Cited by 56 publications

References 10 publications

Delayed Osteoblastic Differentiation and Bone Development in Cx43 Knockout Mice

Delayed Osteoblastic Differentiation and Bone Development in Cx43 Knockout Mice

A Gja1 missense mutation in a mouse model of oculodentodigital dysplasia

A novel truncation mutation in GJA1 associated with open angle glaucoma and microcornea in a large Chinese family

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