Homozygosity mapping identifies the Crumbs homologue 1 (Crb1) gene as responsible for a recessive syndrome of retinitis pigmentosa and nanophthalmos

Abstract

The association of retinitis pigmentosa (RP) and microphthalmia has been reported in a number of familial and isolated cases. Here, the results of genetic analysis in a familial case of early RP associated with nanophthalmos are described. Two affected sibs were ascertained from an endogamous population in Mexico. A genome-wide linkage analysis was performed by means of an Affymetrix 250K microarray. Five large regions of homozygosity were demonstrated. The largest interval comprised 15.08 Mb at chromosome 1q31-32.1 and contained the Crumbs homologue-1, CRB1, a gene responsible for a number of recessive retinal dystrophies. Nucleotide sequence analysis demonstrated a c.1125C>G transversion in CRB1 exon 5, predicting a novel p.Tyr375X variant. To our knowledge this is the first instance in which a CRB1 mutation has been associated with early RP and nanophthalmos. Our results suggest a role for CRB1 in promoting axial growth of the eye. Clinical analysis of additional subjects with retinal dystrophies due to CRB1 mutations will help to identify if the high hyperopia, a frequently observed trait in these subjects, could be related to decreased eye axial length (nanophthalmos).

CRB1 mutations in inherited retinal dystrophies

“…Patients with CRB1 mutations belong to both categories. Predisposition of the CRB1 patients to keratoconus (McKibbin, et al, 2010; McMahon, et al, 2009) and implication for pigmented paravenous chorioretinal atrophy (McKay, et al, 2005) and nanophthalmos (Zenteno, et al, 2011) have also been reported.…”

The Family of Crumbs Genes and Human Disease

“…Other ocular findings associated with pathogenic CRB1 variants include macular atrophy, pigmented paravenous chorioretinal atrophy, and a predisposition to keratoconus and nanophthalmos [den Hollander et al, 2004;McMahon et al, 2009;Henderson et al, 2010;Zenteno et al, 2011;Bujakowska et al, 2012;Pellissier et al, 2015]. CRB1 mutations may also be a rare cause of cystoid macular edema, a condition that has responded favorably to topical carbonic anhydrase inhibitors [Tsang et al, 2014;Wolfson et al, 2015].…”

Detection of CRB1 mutations in families with retinal dystrophy through phenotype-oriented mutational screening

“…The frequency of CRB1 mutations in patients with macular nummular pigmentation was not available due to the unavailability of the frequency of this fundus change in patients analyzed in previous studies. However, macular nummular pigmentation is rarely observed in patients with mutations in other genes, although it has been described in different studies in a number of patients with CRB1 mutations (9,16,24,25,(35)(36)(37). Therefore, it may be considered a characteristic indication for CRB1-associated retinal dystrophy.…”