Coats' disease of the retina (unilateral retinal telangiectasis) caused by somatic mutation in the NDP gene: a role for norrin in retinal angiogenesis

Abstract

Coats' disease is characterized by abnormal retinal vascular development (so-called 'retinal telangiectasis') which results in massive intraretinal and subretinal lipid accumulation (exudative retinal detachment). The classical form of Coats' disease is almost invariably isolated, unilateral and seen in males. A female with a unilateral variant of Coats' disease gave birth to a son affected by Norrie disease. Both carried a missense mutation within the NDP gene on chromosome Xp11.2. Subsequently analysis of the retinas of nine enucleated eyes from males with Coats' disease demonstrated in one a somatic mutation in the NDP gene which was not present within non-retinal tissue. We suggest that Coats' telangiectasis is secondary to somatic mutation in the NDP gene which results in a deficiency of norrin (the protein product of the NDP gene) within the developing retina. This supports recent observations that the protein is critical for normal retinal vasculogenesis.

A population-based study of Coats disease in the United Kingdom I: epidemiology and clinical features at diagnosis

“…Black et al 14 have reported the case of a female with unilateral Coats disease who gave birth to a son with Norrie's disease. Both mother and son carried a missense mutation in the NDP (Norrie) gene on chromosome Xp11.2 leading to speculation that mutations in this gene may be responsible for at least some cases of Coats disease.…”

“…Both mother and son carried a missense mutation in the NDP (Norrie) gene on chromosome Xp11.2 leading to speculation that mutations in this gene may be responsible for at least some cases of Coats disease. 14,15 We have reported the clinical features at presentation of the spectrum of Coats disease presenting over a 12-month period in the United Kingdom. We have confirmed the findings of previous studies that Coats predominantly affects males and that it is usually unilateral and that it preferentially affects younger patients.…”

Coats’ disease: not such a smooth ride

“…As in many other diseases, I do not think there exists a clear boundary between genetic and non-genetic etiology in this condition: this is not familiar as FEVR or clearly geneassigned as NDP in Norrie's (a quoted anecdotal association [4] with this gene has not been confirmed by other studies, despite 20 years of investigation). Nevertheless, several observations of associated gene mutations support the possibility of Coats' disease as a genetic syndrome.…”

Phenotypic heterogeneity associated with a novel mutation (Gly112Glu) in the Norrie disease protein

“…The relationship between genotype and clinical diagnosis becomes even less predictable when one considers that germ line mutations in NDP have been implicated in advanced retinopathy of prematurity (ROP), and somatic mutations have been found in Coats' disease. 35,36 This imprecision in our clinical nomenclature is of more than academic importance. Female carriers of NDP mutations have a significant risk of giving birth to a bilaterally blind child while the literature would suggest that this eventuality would be extremely uncommon (eg 7/216, see above) for a woman affected with FEVR, or Coats' disease.…”