April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
Autosomal Recessive Posterior Microphthalmos/Nanophthalmos is Caused by Loss-of-function Mutations in LOC646960, a Novel Gene Encoding a Trypsin-like Serine Protease
Andreas Gal; I Rau; L El Matri; H-J Kreienkamp; F Munier; J Fuchs; H C. Fledelius; K Vilhelmsen; D A. Thompson; T Rosenberg
Author Affiliations & Notes
  • Andreas Gal
    Inst Human Genetics, Univ Med Ctr Hamburg-Eppendorf, Hamburg, Germany
  • I Rau
    Inst Human Genetics, Univ Med Ctr Hamburg-Eppendorf, Hamburg, Germany
  • L El Matri
    Hedi Rais Inst Ophthalmology, Tunis, Tunisia
  • H-J Kreienkamp
    Inst Human Genetics, Univ Med Ctr Hamburg-Eppendorf, Hamburg, Germany
  • F Munier
    Ophthalmology, Jules Gonin Eye Hospital, Lausanne, Switzerland
  • J Fuchs
    Dept Ophthalmol, Glostrup Hospital, Univ Copenhagen, Glostrup, Denmark
  • H C. Fledelius
    Dept Ophthalmol, Rigshospitalet, Univ Copenhagen, Copenhagen, Denmark
  • K Vilhelmsen
    Natl Hospital Faroe Islands, Torshavn, Faroe Islands
  • D A. Thompson
    Dept Ophthalmol Visual Sci, Univ Michigan Med Sch, Kellogg Eye Ctr, Ann Arbor, Michigan
    Dept Biol Chem, Univ Michigan Med Sch, Ann Arbor, Michigan
  • T Rosenberg
    Gordon Norrie Ctr Genet Eye Dis, Natl Eye Clinic, Kennedy Ctr, Glostrup, Denmark
  • Footnotes
    Commercial Relationships  Andreas Gal, None; I. Rau, None; L. El Matri, None; H-J Kreienkamp, None; F. Munier, None; J. Fuchs, None; H. C. Fledelius, None; K. Vilhelmsen, None; D. A. Thompson, None; T. Rosenberg, None
  • Footnotes
    Support  Genetic Resource Center, Ílegusavnið, Faroe Islands, Danish Society of the Blind, Swiss National Science Foundation (grant # 320030-127558), Research to Prevent Blindness, Midwest Eye Banks
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 1638. doi:
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      Andreas Gal, I Rau, L El Matri, H-J Kreienkamp, F Munier, J Fuchs, H C. Fledelius, K Vilhelmsen, D A. Thompson, T Rosenberg; Autosomal Recessive Posterior Microphthalmos/Nanophthalmos is Caused by Loss-of-function Mutations in LOC646960, a Novel Gene Encoding a Trypsin-like Serine Protease. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1638.

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Abstract

Purpose: : Posterior microphthalmos (MCOP)/nanophthalmos (NNO) is a developmental anomaly characterized by extreme hyperopia due to short axial length. The population of the Faroe Islands shows a high prevalence of an autosomal recessive form (arMCOP). The gene mutated in arMCOP is not yet known.

Methods: : Genetic mapping by linkage analysis using microsatellite and single nucleotide polymorphisms, mutation analysis by PCR and sequencing, molecular modelling

Results: : Having refined the position of the disease locus (MCOP6) in an interval of 250 kb in chromosome 2q37.1 in Faroese families, we detected 3 mutations in a novel gene, LOC646960: Patients of 10 different Faroese families were either homozygous (n=22) for c.926G>C (p.Trp309Ser) or compound heterozygous (n=6) for c.926G>C and c.526C>G (p.Arg176Gly), whereas a homozygous 1 bp duplication (c.1066dupC) was identified in patients with arNNO from a Tunisian family. In two unrelated patients with MCOP, no LOC646960 mutation was found. LOC646960 is expressed in the human adult retina and RPE. The expression of the mouse homologue in the eye can be first detected at E17 and is highest in adults. The predicted protein is a 603 amino acid long secreted trypsin-like serine peptidase. c.1066dupC should result in a functional null allele. Molecular modelling of the p.Trp309Ser mutant suggests that both affinity and reactivity of the enzyme towards in vivo substrates are substantially reduced.

Conclusions: : Postnatal growth of the eye is important for proper development of the refractive components (emmetropization), and is mainly due to elongation of the posterior segment from 10-11 mm at birth to 15-16 mm at the age of 13 years. Optical defocus leads to changes in axial length by moving the retina towards the image plane. arMCOP may theoretically be explained, in line with the expression pattern of LOC646960, by a postnatal growth retardation of the posterior segment.

Keywords: hyperopia • mutations • proteolysis 
© 2011, The Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Permission to republish any abstract or part of an abstract in any form must be obtained in writing from the ARVO Office prior to publication.
Copyright © 2025 Association for Research in Vision and Ophthalmology.
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