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Novel TMEM98 mutations in pedigrees with autosomal dominant nanophthalmos.

Khorram D, Choi M, Roos BR, Stone EM, Kopel T, Allen R, Alward WL, Scheetz TE, Fingert JH - Mol. Vis. (2015)

Bottom Line: Patients with nanophthalmos have high hyperopia (far-sightedness), a greater incidence of angle-closure glaucoma, and increased risk of surgical complications.Testing the Mariana Islands pedigree for TMEM98 mutations identified a 34 bp heterozygous deletion that spans the 3' end of exon 4 in all affected family members.Neither TMEM98 mutation was detected in public exome sequence databases.

View Article: PubMed Central - PubMed

Affiliation: Marianas Eye Institute, Saipan, Northern Mariana Islands.

ABSTRACT

Purpose: Autosomal dominant nanophthalmos is an inherited eye disorder characterized by a structurally normal but smaller eye. Patients with nanophthalmos have high hyperopia (far-sightedness), a greater incidence of angle-closure glaucoma, and increased risk of surgical complications. In this study, the clinical features and the genetic basis of nanophthalmos were investigated in two large autosomal dominant nanophthalmos pedigrees.

Methods: Fourteen members of a Caucasian pedigree from the United States and 15 members of a pedigree from the Mariana Islands enrolled in a genetic study of nanophthalmos and contributed DNA samples. Twenty of 29 family members underwent eye examinations that included measurement of axial eye length and/or refractive error. The genetic basis of nanophthalmos in the pedigrees was studied with linkage analysis, whole exome sequencing, and candidate gene (i.e., TMEM98) sequencing to identify the nanophthalmos-causing gene.

Results: Nine members of the pedigree from the United States and 11 members of the pedigree from the Mariana Islands were diagnosed with nanophthalmos that is transmitted as an autosomal dominant trait. The patients with nanophthalmos had abnormally short axial eye lengths, which ranged from 15.9 to 18.4 mm. Linkage analysis of the nanophthalmos pedigree from the United States identified nine large regions of the genome (greater than 10 Mbp) that were coinherited with disease in this family. Genes within these "linked regions" were examined for disease-causing mutations using exome sequencing, and a His196Pro mutation was detected in the TMEM98 gene, which was recently reported to be a nanophthalmos gene. Sanger sequencing subsequently showed that all other members of this pedigree with nanophthalmos also carry the His196Pro TMEM98 mutation. Testing the Mariana Islands pedigree for TMEM98 mutations identified a 34 bp heterozygous deletion that spans the 3' end of exon 4 in all affected family members. Neither TMEM98 mutation was detected in public exome sequence databases.

Conclusions: A recent report identified a single TMEM98 missense mutation in a nanophthalmos pedigree. Our discovery of two additional TMEM98 mutations confirms the important role of the gene in the pathogenesis of autosomal dominant nanophthalmos.

No MeSH data available.


Related in: MedlinePlus

TMEM98 sequence analysis. Alignment of protein sequences encoded by human TMEM98 with orthologous genes spanning the His196Pro mutation detected in pedigree 991-F. The histidine amino acid at codon 196 indicated in blue letters is conserved across many species; the flanking amino acids that are not conserved are indicated in red.
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f4: TMEM98 sequence analysis. Alignment of protein sequences encoded by human TMEM98 with orthologous genes spanning the His196Pro mutation detected in pedigree 991-F. The histidine amino acid at codon 196 indicated in blue letters is conserved across many species; the flanking amino acids that are not conserved are indicated in red.

Mentions: Sequence analysis of both TMEM98 mutations provided additional support for their pathogenicity. Neither the His196Pro mutation nor the 34 bp deletion was detected in public DNA sequence databases including the Exome Variation Server and the 1000 Genomes Project [14]. Both mutations span highly conserved sequences based on the UCSC Genome Browser and BlastP. The His196Pro mutation detected in pedigree 991-F alters a histidine amino acid that is highly conserved across many disparate species (Figure 4), which provides additional support for the mutation’s potential pathogenicity.


Novel TMEM98 mutations in pedigrees with autosomal dominant nanophthalmos.

Khorram D, Choi M, Roos BR, Stone EM, Kopel T, Allen R, Alward WL, Scheetz TE, Fingert JH - Mol. Vis. (2015)

TMEM98 sequence analysis. Alignment of protein sequences encoded by human TMEM98 with orthologous genes spanning the His196Pro mutation detected in pedigree 991-F. The histidine amino acid at codon 196 indicated in blue letters is conserved across many species; the flanking amino acids that are not conserved are indicated in red.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556162&req=5

f4: TMEM98 sequence analysis. Alignment of protein sequences encoded by human TMEM98 with orthologous genes spanning the His196Pro mutation detected in pedigree 991-F. The histidine amino acid at codon 196 indicated in blue letters is conserved across many species; the flanking amino acids that are not conserved are indicated in red.
Mentions: Sequence analysis of both TMEM98 mutations provided additional support for their pathogenicity. Neither the His196Pro mutation nor the 34 bp deletion was detected in public DNA sequence databases including the Exome Variation Server and the 1000 Genomes Project [14]. Both mutations span highly conserved sequences based on the UCSC Genome Browser and BlastP. The His196Pro mutation detected in pedigree 991-F alters a histidine amino acid that is highly conserved across many disparate species (Figure 4), which provides additional support for the mutation’s potential pathogenicity.

Bottom Line: Patients with nanophthalmos have high hyperopia (far-sightedness), a greater incidence of angle-closure glaucoma, and increased risk of surgical complications.Testing the Mariana Islands pedigree for TMEM98 mutations identified a 34 bp heterozygous deletion that spans the 3' end of exon 4 in all affected family members.Neither TMEM98 mutation was detected in public exome sequence databases.

View Article: PubMed Central - PubMed

Affiliation: Marianas Eye Institute, Saipan, Northern Mariana Islands.

ABSTRACT

Purpose: Autosomal dominant nanophthalmos is an inherited eye disorder characterized by a structurally normal but smaller eye. Patients with nanophthalmos have high hyperopia (far-sightedness), a greater incidence of angle-closure glaucoma, and increased risk of surgical complications. In this study, the clinical features and the genetic basis of nanophthalmos were investigated in two large autosomal dominant nanophthalmos pedigrees.

Methods: Fourteen members of a Caucasian pedigree from the United States and 15 members of a pedigree from the Mariana Islands enrolled in a genetic study of nanophthalmos and contributed DNA samples. Twenty of 29 family members underwent eye examinations that included measurement of axial eye length and/or refractive error. The genetic basis of nanophthalmos in the pedigrees was studied with linkage analysis, whole exome sequencing, and candidate gene (i.e., TMEM98) sequencing to identify the nanophthalmos-causing gene.

Results: Nine members of the pedigree from the United States and 11 members of the pedigree from the Mariana Islands were diagnosed with nanophthalmos that is transmitted as an autosomal dominant trait. The patients with nanophthalmos had abnormally short axial eye lengths, which ranged from 15.9 to 18.4 mm. Linkage analysis of the nanophthalmos pedigree from the United States identified nine large regions of the genome (greater than 10 Mbp) that were coinherited with disease in this family. Genes within these "linked regions" were examined for disease-causing mutations using exome sequencing, and a His196Pro mutation was detected in the TMEM98 gene, which was recently reported to be a nanophthalmos gene. Sanger sequencing subsequently showed that all other members of this pedigree with nanophthalmos also carry the His196Pro TMEM98 mutation. Testing the Mariana Islands pedigree for TMEM98 mutations identified a 34 bp heterozygous deletion that spans the 3' end of exon 4 in all affected family members. Neither TMEM98 mutation was detected in public exome sequence databases.

Conclusions: A recent report identified a single TMEM98 missense mutation in a nanophthalmos pedigree. Our discovery of two additional TMEM98 mutations confirms the important role of the gene in the pathogenesis of autosomal dominant nanophthalmos.

No MeSH data available.


Related in: MedlinePlus