Linkage Analysis Narrows the Critical Region for Oculodentodigital Dysplasia to Chromosome 6q22–q23

doi:10.1006/geno.1999.5814

Genomics

Volume 58, Issue 1, 15 May 1999, Pages 34-40

https://doi.org/10.1006/geno.1999.5814 Get rights and content

Abstract

Oculodentodigital dysplasia (ODDD) is an autosomal dominant condition with high penetrance and variable expressivity. The anomalies of the craniofacial region, eyes, teeth, and limbs indicate abnormal morphogenesis during early fetal development. Neurologic abnormalities occur later in life and appear to be secondary to white matter degeneration and basal ganglia changes. In familial cases, the dysmorphic and/or neurodegenerative components of the phenotype can be more severe and/or present at a younger age in subsequent generations, suggesting genetic anticipation. These clinical features suggest that the ODDD gene is pleiotropic with important functions throughout pre- and postnatal development. We have performed two-point linkage analysis with seven ODDD families and 19 microsatellite markers on chromosome 6q spanning a genetic distance of approximately 11 cM in males and 20 cM in females. We have refined the location of the ODDD gene between DNA markers D6S266/D6S261 (centromeric) and D6S1639 (telomeric), an interval of 1.01 (male) to 2.87 (female) cM. The strongest linkage was to DNA marker D6S433 (Z_max= 8.96, θ_max= 0.001). Families show significant linkage to chromosome 6q22–q23 and no evidence for genetic heterogeneity.

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Syndromic and non-syndromic disease-linked Cx43 mutations
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Citation Excerpt :
ODDD is primarily an autosomal-dominant human disorder where patients display symptoms of congenital craniofacial deformities, anomalies of the teeth and eyes and limb deformities [21–23]. Digital malformations include syndactyly involving the third, fourth and fifth fingers and camptodactyly of the second to fourth toe [21–23]. Most ODDD patients also have mandibular overgrowth, abnormal dentition, enamel hypoplasia and early tooth loss [19].
There are now at least 14 distinct diseases linked to germ line mutations in the 21 genes that encode the connexin (Cx) family of gap junction proteins. This review focuses on the links between germ-line mutations in the gene encoding Cx43 (GJA1) and the human disease termed oculodentodigital dysplasia (ODDD). This disease is clinically characterized by soft tissue fusion of the digits, abnormal craniofacial bone development, small eyes and loss of tooth enamel. However, the disease is considerably more complex and somewhat degenerative as patients often suffer from other syndromic effects that include incontinence, glaucoma, skin diseases and neuropathies that become more pronounced during aging. The challenge continues to be understanding how distinct Cx43 gene mutations cause such a diverse range of tissue phenotypes and pathophysiological changes while other Cx43-rich organs are relatively unaffected. This review will provide an overview of many of these studies and distill some themes and outstanding questions that need to be addressed in the coming years.
Connexin Mutations in Pelizaeus-Merzbacher-Like Disease, Oculodentodigital Dysplasia and Related Diseases
2013, Gap Junctions in the Brain
Connexin Mutations in Pelizaeus-Merzbacher-Like Disease, Oculodentodigital Dysplasia and Related Diseases
2012, Gap Junctions in the Brain: Physiological and Pathological Roles
Gap junctions in inherited human disorders of the central nervous system
2012, Biochimica et Biophysica Acta - Biomembranes
CNS glia and neurons express connexins, the proteins that form gap junctions in vertebrates. We review the connexins expressed by oligodendrocytes and astrocytes, and discuss their proposed physiologic roles. Of the 21 members of the human connexin family, mutations in three are associated with significant central nervous system manifestations. For each, we review the phenotype and discuss possible mechanisms of disease. Mutations in GJB1, the gene for connexin 32 (Cx32) cause the second most common form of Charcot–Marie–Tooth disease (CMT1X). Though the only consistent phenotype in CMT1X patients is a peripheral demyelinating neuropathy, CNS signs and symptoms have been found in some patients. Recessive mutations in GJC2, the gene for Cx47, are one cause of Pelizaeus–Merzbacher-like disease (PMLD), which is characterized by nystagmus within the first 6 months of life, cerebellar ataxia by 4 years, and spasticity by 6 years of age. MRI imaging shows abnormal myelination. A different recessive GJC2 mutation causes a form of hereditary spastic paraparesis, which is a milder phenotype than PMLD. Dominant mutations in GJA1, the gene for Cx43, cause oculodentodigital dysplasia (ODDD), a pleitropic disorder characterized by oculo-facial abnormalities including micropthalmia, microcornia and hypoplastic nares, syndactyly of the fourth to fifth fingers and dental abnormalities. Neurologic manifestations, including spasticity and gait difficulties, are often but not universally seen. Recessive GJA1 mutations cause Hallermann–Streiff syndrome, a disorder showing substantial overlap with ODDD. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and functions.
Differential potency of dominant negative connexin43 mutants in oculodentodigital dysplasia
2007, Journal of Biological Chemistry
Oculodentodigital dysplasia (ODDD) is a congenital autosomal dominant disorder with phenotypic variability, which has been associated with mutations in the GJA1 gene encoding connexin43 (Cx43). Given that Cx43 mutants are thought to be equally co-expressed with wild-type Cx43 in ODDD patients, it is imperative to examine the consequence of these mutants in model systems that reflect this molar ratio. To that end, we used differential fluorescent protein tagging of mutant and wild-type Cx43 to quantitatively monitor the ratio of mutant/wild-type within the same putative gap junction plaques and co-immunoprecipitation to determine if the mutants interact with wild-type Cx43. Together the fluorescence-based assay was combined with patch clamp analysis to assess the dominant negative potency of Cx43 mutants. Our results revealed that the ODDD-linked Cx43 mutants, G21R and G138R, as well as amino terminus green fluorescent protein-tagged Cx43, were able to co-localize with wild-type Cx43 at the gap junction plaque-like structures and to co-immunoprecipitate with wild-type Cx43. All Cx43 mutants demonstrated dominant negative action on gap junctional conductance of wild-type Cx43 but not that of Cx32. More interestingly, these Cx43 mutants demonstrated different potencies in inhibiting the function of wild-type Cx43 with the G21R mutant being two times more potent than the G138R mutant. The potency difference in the dominant negative properties of ODDD-linked Cx43 mutants may have clinical implications for the various symptoms and disease severity observed in ODDD patients.
Novel GJA1 mutations in patients with oculo-dento-digital dysplasia (ODDD)
2005, European Journal of Medical Genetics
Citation Excerpt :
Occasionally mild mental retardation is noticed and diffuse bilateral abnormalities in the white matter may be present on brain magnetic resonance studies. The ODDD locus resides on chromosome 6q22-q24 [1,6] and recently Paznekas et al. [22] reported that ODDD is caused by mutations in GJA1. This gene encodes the gap junction protein alpha 1 (GJA1 or connexin 43).
Oculo-dento-digital dysplasia (ODDD) is an autosomal dominant disorder characterized by developmental anomalies of the face, the eyes, the limbs and the teeth. Patients with ODDD usually present with complete syndactyly of the fourth and fifth fingers (type III syndactyly), ocular changes, abnormalities of primary and permanent dentition and specific craniofacial malformations. Mutations in GJA1, a gene that encodes the gap junction protein connexin 43, are responsible for ODDD. Gap junctions are assemblies of intercellular channels that allow exchange of various ions and signaling molecules between cells. In this way, gap junctions play an important regulatory role in a variety of physiologic and developmental processes. We identified three novel and one previously described GJA1 mutation in two large ODDD families and two sporadic ODDD cases.

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^*: These authors contributed equally to this study.

^†: To whom correspondence may be addressed at Institute of Genetic Medicine, CMSC 1004, 600 North Wolfe St., Baltimore, MD 21287-3914. Telephone: (410) 955-4160. Fax: (410) 955-0484. E-mail:[email protected].

^‡: To whom correspondence may be addressed at Department of Neurology, Given B-211, College of Medicine, University of Vermont, Burlington, VT 05405-0068. Telephone: (802) 656-1480. Fax: (802) 656-5844. E-mail:[email protected].

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Regular ArticleLinkage Analysis Narrows the Critical Region for Oculodentodigital Dysplasia to Chromosome 6q22–q23

Abstract

J. Pediatr.

J. Pediatr.

Am. J. Ophthalmol.

Oral Surg.

Manifestations neurologiques de la dysplasie oculo-dento-osseuse

Rev. Otoneuroophthalmol.

Intracranial calcification in oculodento-osseous dysplasia

S. Afr. Med. J.

Oculo-dento-digital syndrome (Gorlin's syndrome): Clinical and genetic report of a new family

Acta Neurol.

Oculodento-osseous dysplasia: Heterogeneity or variable expression?

Clin. Genet.

Oculodentodigital dysplasia and type III syndactyly: Separate genetic entities or disease spectrum?

J. Med. Genet.

Syndactyly: Frequency of specific types

Am. J. Med. Genet.

A case of syndactylism of the ring and little finger

Am. J. Med. Genet.

Faster sequential genetic linkage computations

Am. J. Hum. Genet.

Neurologic abnormalities in oculodentodigital dysplasia. A new finding

Clin. Res.

“Touchdown” PCR to circumvent spurious priming during gene amplification

Nucleic Acids Res.

Oculo-dento-digital dysplasia

Trans. Ophthal. Soc. UK

A hereditary syndrome: Dysplasia oculodentodigitalis

Arch. Ophthalmol.

Localization of a gene for oculodentodigital syndrome to human chromosome 6q22–q24

Hum. Mol. Genet.

Central nervous system abnormalities in oculodentodigital dysplasia syndrome

Am. J. Med. Genet.

Oculodentodigital dysplasia

Rev. Invest. Clin.

Oculodentodigital dysplasia syndrome associated with abnormal cerebral white matter

Am. J. Med. Genet.

Syndactyly of the ring and little finger

Am. J. Hum. Genet.

Oculodentodigital dysplasia. Four new reports and a literature review

Arch. Ophthalmol.

GLI3 frameshift mutations cause autosomal dominant Pallister–Hall syndrome

Nat. Genet.

Easy calculations of lod scores and genetic risks on small computers

Am. J. Hum. Genet.

The Holmes–Adie syndrome in a boy with acute juvenile rheumatism and bilateral syndactyly

Arch. Dis. Child.

Regular Article
Linkage Analysis Narrows the Critical Region for Oculodentodigital Dysplasia to Chromosome 6q22–q23