Purpose

Nanophthalmos is a rare genetic ocular disorder in which the eyes of affected individuals are abnormally small. Patients suffer from severe hyperopia as a result of their markedly reduced axial lengths, but otherwise are capable of seeing well unlike other more general forms of microphthalmia. To date one gene for nanophthalmos has been identified, encoding the membrane-type frizzled related protein MFRP. Identification of additional genes for nanophthalmos will improve our understanding of normal developmental regulation of eye growth.

Methods

We ascertained a cohort of families from eastern Canada and Mexico with familial nanophthalmos. We performed high density microsatellite and high density single nucleotide polymorphism (SNP) genotyping to identify potential chromosomal regions of linkage. We sequenced coding regions of genes in the linked interval by traditional PCR-based Sanger capillary electrophoresis methods. We cloned and sequenced a novel cDNA from a putative causal gene to verify gene structure.

Results

We identified a linked locus on chromosome 2q37 with a peak logarithm (base 10) of odds (LOD) score of 4.7. Sequencing of coding exons of all genes in the region identified multiple segregating variants in one gene, recently annotated as serine protease gene (PRSS56), coding for a predicted trypsin serine protease-like protein. One of our families was homozygous for a predicted pathogenic missense mutation, one family was compound heterozygous for two predicted pathogenic missense mutations, and one family was compound heterozygous for a predicted pathogenic missense mutation plus a frameshift leading to obligatory truncation of the predicted protein. The PRSS56 gene structure in public databases is based on a virtual transcript assembled from overlapping incomplete cDNA clones; we have now validated the structure of a full-length transcript from embryonic mouse brain RNA.

Conclusions

PRSS56 is a good candidate for the causal gene for nanophthalmos in our families.

Purpose

We describe the clinical phenotype of a Mexican family segregating Duane syndrome as an autosomal dominant trait linked to chromosome 2q31 (DURS2) and previously reported to harbor a heterozygous α2-chimaerinmissense mutation.

Methods

A five-generation Mexican family was analyzed. Ten affected subjects were available for clinical examination. Participating subjects were tested for visual acuity, ocular alignment by prism cover testing, ocular ductions and versions, and globe retraction. In children, alignment was measured with the Krimsky test in cardinal positions of gaze.

Results

Ten cases were included, 6 females and 4 males. Five cases presented with bilateral and 5 with unilateral Duane syndrome. Right side was the most commonly affected side on unilateral cases. Five cases exhibited exotropia, 4 esotropia, and 1 hypotropia. Seven patients had important limitation of abduction; two, moderate limitation. Four patients had mild adduction limitation and 4 had moderate limitation. No additional anomalies such as fourth (trochlear) nerve palsy, blepharoptosis, or dense amblyopia, reported in previous Duane syndrome families, were observed. All 3 cases that exhibited vertical dysfunction had upgaze limitation. One instance of nonpenetrance was recorded.

Conclusions

Considerable intrafamilial clinical variability was observed in this Duane syndrome pedigree carrying a α2-chimaerin mutation. The presence of bilateral involvement and associated vertical movements, commonly observed in this and others DURS2 families, could suggest the occurrence of CHN1 mutations as the source of the disease in isolated or familial DURS cases.

The RacGAP molecule α2-chimaerin is implicated in neuronal signaling pathways required for precise guidance of developing corticospinal axons. We now demonstrate that a variant of Duane’s retraction syndrome, a congenital eye movement disorder in which affected individuals show aberrant development of axon projections to the extraocular muscles, can result from gain-of-function heterozygous missense mutations in CHN1 that increase α2-chimaerin RacGAP activity in vitro. A subset of mutations enhances α2-chimaerin membrane translocation and/or α2-chimaerin’s previously unrecognized ability to form a complex with itself. In ovo expression of mutant CHN1 alters the development of ocular motor axons. These data demonstrate that human CHN1 mutations can hyperactivate α2-chimaerin and result in aberrant cranial motor neuron development.