Detection of mutations in LRPAP1, CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2 in 298 families with early-onset high myopia by exome sequencing

Invest Ophthalmol Vis Sci. 2014 Dec 18;56(1):339-45. doi: 10.1167/iovs.14-14850.


Purpose: To evaluate variants in the LRPAP1, CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2 genes in 298 unrelated patients with early-onset high myopia (eoHM).

Methods: Genomic DNA from 298 patients with eoHM was analyzed by whole exome sequencing. Variants in LRPAP1, CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2 genes were selected and analyzed with bioinformatics. Potential candidate variants were confirmed by Sanger sequencing and then validated in available family members and 192 healthy controls.

Results: A total of nine variants predicted to affect the functional residues were detected. The LRPAP1 gene showed a homozygous frameshift mutation (c.199delC, p.Q67Sfs*8) in a consanguineous family. The ZNF644 gene showed five heterozygous missense mutations (c.1106A>T, p.K369M; c.1648G>A, p.A550T; c.2014A>G, p.S672G; c.2048G>C, p.R683T, and c.2551G>C, p.D851H) in five families, but the c.1106A>T, (p.K369M) and c.1648G>A, (p.A550T) in ZNF644 did not co-segregated with high myopia in the families and should be excluded as causative mutations. The SLC39A5 gene showed a heterozygous missense variant (c.1238G>C, p.G413A) in a sporadic individual. The SCO2 gene showed two heterozygous missense variants (c.334C>T, p.R112W and c.358C>T, p.R120W) in two families. None of the variants was detected in 192 healthy controls and all were predicted to be damaging by both Polyphen-2 and SIFT, except for the previously reported p.S672G mutation in ZNF644, which was predicted to be damaging by SIFT but benign by Polyphen-2. No homozygous or compound heterozygous variants were found in CTSH and LEPREL1.

Conclusions: Our results provide additional evidence to support the idea that mutation in LRPAP1 is associated with high myopia. Further studies are expected to evaluate the pathogenicity of the variants in CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2.

Keywords: LRPAP1; SCO2; SLC39A5; ZNF644; high myopia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cathepsin H / genetics
  • Cathepsin H / metabolism
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism
  • Child
  • Child, Preschool
  • DNA / genetics*
  • DNA Mutational Analysis
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Exome
  • Eye Proteins / genetics*
  • Eye Proteins / metabolism
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Leucine Zippers
  • Male
  • Middle Aged
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Molecular Chaperones
  • Mutation*
  • Myopia / genetics*
  • Myopia / metabolism*
  • Pedigree
  • Procollagen-Proline Dioxygenase / genetics
  • Procollagen-Proline Dioxygenase / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Young Adult
  • Zinc Fingers


  • CENPI protein, human
  • Carrier Proteins
  • Cation Transport Proteins
  • DNA-Binding Proteins
  • Eye Proteins
  • Mitochondrial Proteins
  • Molecular Chaperones
  • SCO2 protein, human
  • SLC39A5 protein, human
  • Transcription Factors
  • ZNF644 protein, human
  • DNA
  • Procollagen-Proline Dioxygenase
  • P3H2 protein, human
  • CTSH protein, human
  • Cathepsin H