Microphthalmia, Isolated, With Coloboma 10

A number sign (#) is used with this entry because of evidence that isolated microphthalmia and/or coloboma (MCOPCB10) is caused by heterozygous mutation in the RBP4 gene (180250) on chromosome 10q23.

Clinical Features

Chou et al. (2015) studied a 7-generation pedigree in which 11 family members had microphthalmia or clinical anophthalmia and/or coloboma. The first proband was an 8-year-old girl with bilateral clinical anophthalmia in whom MRI at day 1 of life showed bilateral absence of the eyeballs, with only cystic remnants in the orbits, thin optic nerves, and a small chiasm; there were no brain abnormalities. The right orbital cyst was surgically removed at 8 months; pathology revealed rudimentary eye structures. The second proband was an 11-year-old boy, a second cousin of the first proband, with left clinical anophthalmia and right microphthalmia with ventronasal iris and chorioretinal coloboma. Brain MRI and echocardiography at age 7 years were normal. His mother, who was a monozygous twin, had inferior iris and chorioretinal coloboma. The colobomas in both mother and son involved the entire uveal and neuroretinal axis, from the pupillary margin to the optic nerve head. The mother's twin sister, who had normal eyes, was the mother of a 13-year-old boy who had a left-sided iris and chorioretinal coloboma, as well as an atrial septal defect. In another branch of the family, a 61-year-old man had bilateral clinical anophthalmia but was otherwise healthy. In the third generation of the pedigree, 6 deceased individuals reportedly had had anophthalmia/microphthalmia and/or coloboma. Chou et al. (2015) described a second family in which a 41-year-old man had bilateral clinical anophthalmia as well as developmental delay and seizures; his 21-year-old male first cousin once removed also had severe bilateral microphthalmia and similar developmental delay and seizures. In a third family, a mother exhibited only unilateral optic pit, but her 12-year-old daughter had left-sided microphthalmia and ventronasal iris coloboma.

Mapping

In a 7-generation family in which 11 members had microphthalmia or clinical anophthalmia and/or coloboma, Chou et al. (2015) excluded 23 known loci associated with microphthalmia and coloboma. By genomewide multipoint linkage analysis, the authors identified a nonrecombinant 8.2-Mb interval on chromosome 10q23 with a peak lod score of 3.01.

Inheritance

The transmission pattern of microphthalmia or clinical anophthalmia and/or coloboma in the 7-generation family reported by Chou et al. (2015) was consistent with autosomal dominant inheritance. Maternal penetrance was significantly greater than paternal inheritance (0.7 vs 0.1).

Molecular Genetics

In a 7-generation family segregating microphthalmia or clinical anophthalmia and/or coloboma mapping to chromosome 10q23, Chou et al. (2015) analyzed 3 candidate genes in the critical region that have roles in vitamin A transport. They identified a missense mutation in the RBP4 gene (A75T; 180250.0004) that segregated with the disease and was not found in more than 11,330 control chromosomes. All but 1 of the 11 affected individuals inherited the trait from their mother; thus, maternal penetrance was significantly greater than paternal penetrance (0.7 vs 0.1). In the 1 instance of paternal transmission, only 1 of 2 monozygous twins was affected. Screening of DNA samples from 75 unrelated microphthalmia/coloboma cases revealed another RBP4 missense mutation (A73T; 180250.0005) in 2 patients; the mutation occurred on distinct haplotypes, indicating recurrence, and there was maternal transmission in both families. Functional analysis demonstrated that both mutant retinol-binding proteins (RBPs) bind the STRA6 (610745) receptor with much higher affinity than wildtype yet carry little or no vitamin A. Consistent with these findings, all 3 A75T heterozygous carriers who were tested had fasting serum vitamin A levels below normal limits, and plasma retinol fluorescence was also reduced. Chou et al. (2015) suggested that the significantly greater penetrance in this disorder when the RBP4 mutation is maternally transmitted results from decreased vitamin A delivery both at the placenta, involving maternal-derived RBP, and later at the developing eye primordia, involving fetal-derived RBP.