title: Mutations in a novel serine protease PRSS56 in families with nanophthalmos.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada. aorr@dal.ca
authors.forename: Andrew
authors.initials: A
authors.lastname: Orr
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Dubé
authors.forename: Juan C
authors.initials: JC
authors.lastname: Zenteno
authors.forename: Haiyan
authors.initials: H
authors.lastname: Jiang
authors.forename: Geraldine
authors.initials: G
authors.lastname: Asselin
authors.forename: Susan C
authors.initials: SC
authors.lastname: Evans
authors.forename: Aurore
authors.initials: A
authors.lastname: Caqueret
authors.forename: Hesham
authors.initials: H
authors.lastname: Lakosha
authors.forename: Louis
authors.initials: L
authors.lastname: Letourneau
authors.forename: Julien
authors.initials: J
authors.lastname: Marcadier
authors.forename: Makoto
authors.initials: M
authors.lastname: Matsuoka
authors.forename: Christine
authors.initials: C
authors.lastname: Macgillivray
authors.forename: Mathew
authors.initials: M
authors.lastname: Nightingale
authors.forename: Simon
authors.initials: S
authors.lastname: Papillon-Cavanagh
authors.forename: Scott
authors.initials: S
authors.lastname: Perry
authors.forename: Sylvie
authors.initials: S
authors.lastname: Provost
authors.forename: Mark
authors.initials: M
authors.lastname: Ludman
authors.forename: Duane L
authors.initials: DL
authors.lastname: Guernsey
authors.forename: Mark E
authors.initials: ME
authors.lastname: Samuels
mesh_terms: D000818:Animals; D001483:Base Sequence; D002170:Canada; D003001:Cloning, Molecular; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005091:Exons; D005123:Eye / Q000473:pathology / Q000503:physiopathology*; D008040:Genetic Linkage; D005838:Genotype; D060005:Genotyping Techniques; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006956:Hyperopia / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008126:Lod Score; D008565:Membrane Proteins / Q000235:genetics; D008800:Mexico; D051379:Mice; D008850:Microphthalmos / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D057057:Serine Proteases / Q000235:genetics; D000099274:Frizzled-Related Proteins
chemical_list: D008565:Membrane Proteins; D057057:Serine Proteases; C490110:MFRP protein, human; D000099274:Frizzled-Related Proteins; C558176:PRSS56 protein, human