A mutation in DOP1B identified as a probable cause for autosomal recessive Peters anomaly in a consanguineous family

Abstract

Purpose: Peters anomaly (PA) is a heterogeneous developmental disorder characterized by central corneal opacity and iridocorneal or corneolenticular adhesions. Although many causative genes have been identified, most screened patients do not have mutations in the known genes. We aimed to identify the genetic cause of Peters anomaly in a pedigree with three affected individuals.

Methods: Slit-lamp biomicroscopy and ultrasound biomicroscopy were performed for definitive diagnosis. Exome sequencing was conducted on the DNA of all three patients. After identification of a candidate causative gene, expression of the gene was assessed with real-time PCR in various ocular tissues of three human embryos and three adults.

Results: The patients were affected with isolated PA. The parents of the patients were related to one another. Inheritance of PA was autosomal recessive. After appropriate filtering of the exome data, a homozygous variation in DOP1B remained as the only candidate genetic cause of PA in the pedigree. The variant segregated with disease status in the pedigree and was absent among 800 control Iranians. The variant has been reported in various databases at frequencies of 0.006 or less only in the heterozygous state in some cohorts of African origin. The p.Val1660 amino acid affected by the mutation is completely conserved in mammals and birds during evolution. Expression of DOP1B was shown in all adult and embryonic lens, iris, cornea, sclera, and retina tissues that were tested.

Conclusions: DOP1B that encodes DOP1 leucine zipper like protein B was identified as the putative PA-causing gene in pedigree PA-101. As DOP1B is positioned within the Down syndrome chromosomal region on chromosome 21, until now this gene has mostly been studied with respect to brain functions. However, members of the Dopey gene family have been shown to have roles in development in other organisms. Evidence of the expression of DOP1B in various PA-relevant eye tissues, which, to the best of our knowledge, is shown here for the first time, is to be noted. However, this finding does not necessarily implicate a specific role for DOP1B in eye development as the gene is expressed in many tissues. Ultimately, definitive assessment of the contribution of DOP1B to PA pathology awaits identification of mutations in the gene in unrelated patients with PA and functional studies.

Figure 1

Peters anomaly pedigree PA-101. A: Pedigree PA-101. Filled square and circles: PA-affected. Unfilled shapes: not affected with PA. B: Chromatograms showing homozygous and heterozygous mutation c.4978G>A (p.Val1660Ile) in DOP1B, and the wild-type genotype. C: Amino acid sequence alignments showing conservation of Val at positions corresponding to p.1660 in the human DOP1B-encoded protein in orthologous proteins of other organisms.

Figure 2

Slit-lamp biomicroscopy images show the Peters anomaly. A: PA-101-VI4. B: PA-101-VI5. C: PA-101-VII2. The images of PA-101-VI4 and PA-101-VI5 show total corneal opacity and vascularization. The image of PA-101-VII2 shows total corneal opacity and superficial keratinization.

Figure 3

Ultrasound biomicroscopy images show the Peters anomaly. A: PA-101-VI4. B: PA-101-VI5. Images of both patients show iridocorneal adhesion (arrows).

Figure 4

Expression of DOP1B in adult and embryonic ocular tissues as assessed with real-time PCR. Relative expression levels are presented as normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression. The average threshold cycle (CT) of GAPDH was 16.21. The expression of DOP1B was assessed in the cornea, lens, retina, sclera, and iris tissues of three adult men and three embryos. Standard deviations are shown.