Limits...
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

Diagram of the overlapping regions of chromosome 17 that are coinherited with nanophthalmos in the pedigrees (991-F and 951-N) and in the Awadalla and coworkers’ pedigree [4].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4556162&req=5

f3: Diagram of the overlapping regions of chromosome 17 that are coinherited with nanophthalmos in the pedigrees (991-F and 951-N) and in the Awadalla and coworkers’ pedigree [4].

Mentions: DNA from 20 affected family members of pedigrees 991-F and 951-N was genotyped at 6,020 SNPs. The genotypes were evaluated for coinheritance with nanophthalmos using linkage analysis. In pedigree 991-F, a 20.2 Mbp segment of chromosome 17p12-q12, bounded by SNPs rs530664 and rs16523, was transmitted with nanophthalmos in all members of the family. An overlapping 19.7 Mb section of chromosome 17, bounded by SNPs rs917541 and rs16523, was similarly coinherited with nanophthalmos in pedigree 951-N. These data suggest that the gene that causes autosomal dominant nanophthalmos in pedigrees 991-F and 951-N lies between SNPs rs917541 and rs16523 on chromosome 17 (Figure 3). This pericentric region of chromosome 17 has previously been linked to autosomal dominant nanophthalmos in a Chinese pedigree [8].


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)

Diagram of the overlapping regions of chromosome 17 that are coinherited with nanophthalmos in the pedigrees (991-F and 951-N) and in the Awadalla and coworkers’ pedigree [4].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Diagram of the overlapping regions of chromosome 17 that are coinherited with nanophthalmos in the pedigrees (991-F and 951-N) and in the Awadalla and coworkers’ pedigree [4].
Mentions: DNA from 20 affected family members of pedigrees 991-F and 951-N was genotyped at 6,020 SNPs. The genotypes were evaluated for coinheritance with nanophthalmos using linkage analysis. In pedigree 991-F, a 20.2 Mbp segment of chromosome 17p12-q12, bounded by SNPs rs530664 and rs16523, was transmitted with nanophthalmos in all members of the family. An overlapping 19.7 Mb section of chromosome 17, bounded by SNPs rs917541 and rs16523, was similarly coinherited with nanophthalmos in pedigree 951-N. These data suggest that the gene that causes autosomal dominant nanophthalmos in pedigrees 991-F and 951-N lies between SNPs rs917541 and rs16523 on chromosome 17 (Figure 3). This pericentric region of chromosome 17 has previously been linked to autosomal dominant nanophthalmos in a Chinese pedigree [8].

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