A Novel Mutation in the GJA1 Gene in a Family With Oculodentodigital Dysplasia

Vasconcellos, José Paulo Cabral de; Melo, Mônica Barbosa de; Schimiti, Rui Barroso; Bressanim, Norisvaldo C.; Costa, Fernando Ferreira; Costa, Vital Paulino

doi:10.1001/archopht.123.10.1422

Cited by 45 publications

(24 citation statements)

References 25 publications

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“…These mice carry a G60S amino acid substitution in the first extracellular loop of Cx43, one residue removed from the P59H mutation identified in some human ODDD patients [20]. Consistent with in vitro studies, Cx43…”

Section: Introductionsupporting

confidence: 63%

A Dominant Loss-of-Function GJA1 (Cx43) Mutant Impairs Parturition in the Mouse1

Tong

Wang

et al. 2009

Biology of Reproduction

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Section: Introductionsupporting

confidence: 63%

A Dominant Loss-of-Function GJA1 (Cx43) Mutant Impairs Parturition in the Mouse1

Tong

Wang

et al. 2009

Biology of Reproduction

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“…Jrt allele) in the first extracellular loop of Cx43, which is one residue away from the P59H mutation identified in human ODDD patients (Vasconcellos et al, 2005). Our previous work demonstrated that the granulosa cells isolated from these mice (Gja1 Jrt /+) exhibit either very weak coupling (10-20% versus wild type) or a complete lack of coupling, indicating that the G60S mutant dominantly inhibits the function of co-expressed wild-type Cx43 in vivo (Flenniken et al, 2005).…”

Section: Discussionmentioning

confidence: 95%

Oogenesis defects in a mutant mouse model of oculodentodigital dysplasia

Tong¹,

Colley²,

Thoo³

et al. 2009

Disease Models &Amp; Mechanisms

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SUMMARY The essential role of connexin43 (Cx43) during oogenesis has been demonstrated by the severe germ cell deficiency and arrested folliculogenesis observed in Cx43 knockout mice. Recently, another mutant mouse strain became available (Gja1Jrt/+) that carries the dominant loss-of-function Cx43 mutation, Cx43G60S. Gja1Jrt/+ mice display features of the human disease oculodentodigital dysplasia (ODDD), which is caused by mutations in the GJA1 gene. We used this new mutant strain to study how a disease-linked Cx43 mutant affects oogenesis. We found that female mutant mice are subfertile with significantly reduced mating success and small litters. The phosphorylated species of the Cx43 protein are reduced in the mutant ovaries in association with impaired trafficking and assembly of gap junctions in the membranes of granulosa cells, confirming that the mutant protein acts dominantly on its wild-type counterpart. Correspondingly, although starting with a normal abundance of germ cells, ovaries of the mutant mice contain significantly fewer pre-ovulatory follicles and do not respond to superovulation by gonadotropins, which is at least partially the result of reduced proliferation and increased apoptosis of granulosa cells. We conclude that the Gja1Jrt mutation has a dominant negative effect on Cx43 function in the ovary, rendering the females subfertile. Given these findings, closer examination of reproductive function in ODDD human females is warranted.

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“…eye disorders (Debeer et al, 2005) including glaucoma (Vasconcellos et al, 2005) [see also Table 3 of Loddenkemper et al (Loddenkemper et al, 2002)]. A mouse model of ODDD with a G60S mutation in Cx43 also shows eye abnormalities (Flenniken et al, 2005).…”

Section: Oddd Patients With Different Cx43 Mutations Show Variablementioning

confidence: 99%

Connexin43 is required for production of the aqueous humor in the murine eye

Calera

Topley

Liao

et al. 2006

Journal of Cell Science

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Connexin43 is a major component of the gap junctions between pigmented and non-pigmented cells of the double-layered epithelium in the ciliary body of the eye. We directly tested the hypothesis that gap junctions play a crucial role in the production of the aqueous humor by inactivating the GJA1 (connexin43) gene in the pigmented epithelium with cre-loxP technology. To accomplish this, we crossed a line expressing cre recombinase driven by the nestin promoter and a line with floxed connexin43 alleles. Resultant lines exhibited loss of connexin43 from the pigmented epithelium, iris, retinal pigment epithelium and the lens. We observed plasma proteins in the aqueous humor and pathological changes consistent with a loss of intraocular pressure. As the ciliary body is responsible for aqueous humor production, these data support the hypothesis that the gap junctions between pigmented and non-pigmented epithelium are necessary for production of the aqueous humor that is in turn required for the generation of normal intraocular pressure and nourishment of the postnatal lens. The loss of connexin43 expression in the iris correlated with a separation of the posterior pigmented epithelium from the anterior myoepithelium and with meiosis, possibly resulting from a loss of function of the dilator pupillae.

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A Novel Mutation in the GJA1 Gene in a Family With Oculodentodigital Dysplasia

Cited by 45 publications

References 25 publications

A Dominant Loss-of-Function GJA1 (Cx43) Mutant Impairs Parturition in the Mouse1

A Dominant Loss-of-Function GJA1 (Cx43) Mutant Impairs Parturition in the Mouse1

Oogenesis defects in a mutant mouse model of oculodentodigital dysplasia

Connexin43 is required for production of the aqueous humor in the murine eye

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