GJA1 mutations, variants, and connexin 43 dysfunction as it relates to the oculodentodigital dysplasia phenotype

William A. Paznekas, Barbara Karczeski, Sascha Vermeer, R. Brian Lowry, Martin Delatycki, Faivre Laurence, Pasi A. Koivisto, Lionel Van Maldergem, Simeon A. Boyadjiev, Joann N Bodurtha, Ethylin Wang Jabs

Research output: Contribution to journalArticle

Abstract

The predominantly autosomal dominant disorder, oculodentodigital dysplasia (ODDD) has high penetrance with intra-and interfamilial phenotypic variability. Abnormalities observed in ODDD affect the eye, dentition, and digits of the hands and feet. Patients present with a characteristic facial appearance, narrow nose, and hypoplastic alae nasi. Neurological problems, including dysarthria, neurogenic bladder disturbances, spastic paraparesis, ataxia, anterior tibial muscle weakness, and seizures, are known to occur as well as conductive hearing loss, cardiac defects, and anomalies of the skin, hair, and nails. In 2003, our analysis of 17 ODDD families revealed that each had a different mutation within the human gap junction alpha 1 (GJA1) gene which encodes the protein connexin 43 (Cx43). Since then at least 17 publications have identified an additional 26 GJA1 mutations and in this study, we present 28 new cases with 18 novel GJA1 mutations. We include tables summarizing the 62 known GJA1 nucleotide changes leading to Cx43 protein alterations and the phenotypic information available on 177 affected individuals from 54 genotyped families. Mutations resulting in ODDD occur in each of the nine domains of the Cx43 protein, and we review our functional experiments and those in the literature, examining the effects of 13 different Cx43 mutations upon gap junction activity.

Original languageEnglish (US)
Pages (from-to)724-733
Number of pages10
JournalHuman Mutation
Volume30
Issue number5
DOIs
StatePublished - May 2009
Externally publishedYes

Fingerprint

Connexin 43
Gap Junctions
Phenotype
Mutation
Spastic Paraparesis
Conductive Hearing Loss
Dysarthria
Neurogenic Urinary Bladder
Proteins
Dentition
Penetrance
Muscle Weakness
Nails
Nose
Hair
Publications
Foot
Skeletal Muscle
Seizures
Nucleotides

Keywords

  • Cleft palate
  • Connexin
  • Cx43
  • GJA1
  • Glaucoma
  • Hallermann-Streiff syndrome
  • Hearing loss
  • Neurodegeneration
  • Oculodentodigital dysplasia
  • ODDD

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Paznekas, W. A., Karczeski, B., Vermeer, S., Lowry, R. B., Delatycki, M., Laurence, F., ... Jabs, E. W. (2009). GJA1 mutations, variants, and connexin 43 dysfunction as it relates to the oculodentodigital dysplasia phenotype. Human Mutation, 30(5), 724-733. https://doi.org/10.1002/humu.20958

GJA1 mutations, variants, and connexin 43 dysfunction as it relates to the oculodentodigital dysplasia phenotype. / Paznekas, William A.; Karczeski, Barbara; Vermeer, Sascha; Lowry, R. Brian; Delatycki, Martin; Laurence, Faivre; Koivisto, Pasi A.; Van Maldergem, Lionel; Boyadjiev, Simeon A.; Bodurtha, Joann N; Jabs, Ethylin Wang.

In: Human Mutation, Vol. 30, No. 5, 05.2009, p. 724-733.

Research output: Contribution to journalArticle

Paznekas, WA, Karczeski, B, Vermeer, S, Lowry, RB, Delatycki, M, Laurence, F, Koivisto, PA, Van Maldergem, L, Boyadjiev, SA, Bodurtha, JN & Jabs, EW 2009, 'GJA1 mutations, variants, and connexin 43 dysfunction as it relates to the oculodentodigital dysplasia phenotype', Human Mutation, vol. 30, no. 5, pp. 724-733. https://doi.org/10.1002/humu.20958
Paznekas, William A. ; Karczeski, Barbara ; Vermeer, Sascha ; Lowry, R. Brian ; Delatycki, Martin ; Laurence, Faivre ; Koivisto, Pasi A. ; Van Maldergem, Lionel ; Boyadjiev, Simeon A. ; Bodurtha, Joann N ; Jabs, Ethylin Wang. / GJA1 mutations, variants, and connexin 43 dysfunction as it relates to the oculodentodigital dysplasia phenotype. In: Human Mutation. 2009 ; Vol. 30, No. 5. pp. 724-733.
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