Abstract
Oculodentodigital dysplasia syndrome is associated with numerous pathogenic variants in GJA1, the gene encoding connexin43 gap junction protein. A novel in-frame deletion (p.Lys134del) was found in our clinic. The patient showed all the typical dysmorphic features of the syndrome. The functional consequences of this variant were also studied in an in vitro system. Cells expressed significantly less number of gap junction plaques with a great number of them retained intracellularly.
Highlights
Oculodentodigital dysplasia (ODDD) syndrome is a rare disease with an estimated prevalence < 1/1,000,000
We describe the first cases of ODDD in Cyprus caused by a novel Gap Junction Alpha1 (GJA1) pathogenic variant and clarify the cellular mechanisms of the disease
Intra-familial variability as described in other ODDD families (Loddenkemper et al, 2002; Paznekas et al, 2009) is suggested by the more severe manifestations and earlier diagnosis in the daughter; the mother retrospectively presented with similar symptoms in childhood but remained undiagnosed until her daughter came to medical attention
Summary
Oculodentodigital dysplasia (ODDD) syndrome is a rare disease with an estimated prevalence < 1/1,000,000. It is characterized by nystagmus; microphthalmus; microcornea; anteverted nostrils; syndactyly of the third, fourth, and fifth digits; craniofacial deformities; skin abnormalities; and dental anomalies (Paznekas et al, 2003). ODDD results from autosomal dominant Gap Junction Alpha (GJA1) gene pathogenic variants encoding connexin (Cx43). Each connexin is composed of four trans-membrane domains, N-terminal domain, C-terminal domain, one intracellular, and two extracellular loops (Sohl and Willecke, 2004). The C-terminal tail of Cx43 is long and highly conserved It plays a role in regulating pH whereas the N-terminal domain plays a role in the channel’s state between open and closed. More than 70 different nonsense and missense variants that give rise to
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