Autosomal-recessive posterior microphthalmos is caused by mutations in PRSS56, a gene encoding a trypsin-like serine...

Area of Science:

• Ophthalmology
• Human Genetics
• Molecular Biology

Background:

• Posterior microphthalmos (MCOP) is a rare developmental eye anomaly characterized by extreme hyperopia due to a short axial length.
• A high prevalence of the autosomal-recessive form (arMCOP) is observed in the Faroe Islands population.

Purpose of the Study:

• To refine the disease locus (MCOP6) for arMCOP in Faroese families.
• To identify the genetic cause of arMCOP by analyzing mutations in the PRSS56 gene.
• To investigate the expression pattern of PRSS56 in ocular tissues.

Main Methods:

• Linkage analysis was performed on two large Faroese families to refine the MCOP6 locus to a 250 kb interval on chromosome 2q37.1.
• PRSS56 gene sequencing was conducted on patients from Faroese and Tunisian families to identify mutations.
• RT-PCR was used to detect PRSS56 transcripts in human ocular tissues and mouse eye development.

Main Results:

• Three distinct mutations in the PRSS56 gene were identified: c.926G>C (p.Trp309Ser), c.526C>G (p.Arg176Gly), and c.1066dupC.
• The c.1066dupC mutation was found in a consanguineous Tunisian family, while Faroese families carried homozygous or compound heterozygous mutations.
• PRSS56 transcripts were detected in adult human retina, cornea, sclera, and optic nerve, with expression starting in mouse eyes at E17.

Conclusions:

• Mutations in the PRSS56 gene are a significant cause of autosomal-recessive posterior microphthalmos.
• The identified mutations likely impair the function of the PRSS56 serine peptidase, leading to MCOP.
• Nonallelic heterogeneity is suggested by cases of MCOP without PRSS56 mutations, indicating other genes may also be involved.