Limits...
Variants in Nebulin (NEB) Are Linked to the Development of Familial Primary Angle Closure Glaucoma in Basset Hounds.

Ahram DF, Grozdanic SD, Kecova H, Henkes A, Collin RW, Kuehn MH - PLoS ONE (2015)

Bottom Line: Using exome-sequencing analysis, a possibly damaging, non-synonymous variant in the gene Nebulin (NEB) was found to segregate with PACG which alters a phylogenetically conserved Lysine residue.Nebulin, a protein that promotes the contractile function of sarcomeres, was found to be prominently expressed in the ciliary muscles of the anterior segment.The phenotypic similarities of disease presentation in dogs and humans may enable the translation of findings made in this study to patients with PACG.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA, United States of America.

ABSTRACT
Several dog breeds are susceptible to developing primary angle closure glaucoma (PACG), which suggests a genetic basis for the disease. We have identified a four-generation Basset Hound pedigree with characteristic autosomal recessive PACG that closely recapitulates PACG in humans. Our aim is to utilize gene mapping and whole exome sequencing approaches to identify PACG-causing sequence variants in the Basset. Extensive clinical phenotyping of all pedigree members was conducted. SNP-chip genotyping was carried out in 9 affected and 15 unaffected pedigree members. Two-point and multipoint linkage analyses of genome-wide SNP data were performed using Superlink-Online SNP-1.1 and a locus was mapped to chromosome 19q with a maximum LOD score of 3.24. The locus contains 12 Ensemble predicted canine genes and is syntenic to a region on chromosome 2 in the human genome. Using exome-sequencing analysis, a possibly damaging, non-synonymous variant in the gene Nebulin (NEB) was found to segregate with PACG which alters a phylogenetically conserved Lysine residue. The association of this variants with PACG was confirmed in a secondary cohort of unrelated Basset Hounds (p = 3.4 × 10-4, OR = 15.3 for homozygosity). Nebulin, a protein that promotes the contractile function of sarcomeres, was found to be prominently expressed in the ciliary muscles of the anterior segment. Our findings may provide insight into the molecular mechanisms that underlie PACG. The phenotypic similarities of disease presentation in dogs and humans may enable the translation of findings made in this study to patients with PACG.

No MeSH data available.


Related in: MedlinePlus

Graphical representation of two-point and multipoint linkage analysis results.The larger locus identified with using multipoint linkage analysis a maximum LODmultipoint score of 3.24 (Chr19: 54,949,124–56,765,346) brackets the region identified using two-point linkage analysis (Chr19: 55,358,186–55,848,473) and contains a total of 12 Ensemble-predicted canine genes. Comparison of the linked locus to the human genome reveals shared synteny with a region on chromosome 2. The number and order of genes identified within the canine locus are completely conserved in the syntenic human region.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4418656&req=5

pone.0126660.g003: Graphical representation of two-point and multipoint linkage analysis results.The larger locus identified with using multipoint linkage analysis a maximum LODmultipoint score of 3.24 (Chr19: 54,949,124–56,765,346) brackets the region identified using two-point linkage analysis (Chr19: 55,358,186–55,848,473) and contains a total of 12 Ensemble-predicted canine genes. Comparison of the linked locus to the human genome reveals shared synteny with a region on chromosome 2. The number and order of genes identified within the canine locus are completely conserved in the syntenic human region.

Mentions: Using genome-wide, two-point linkage analysis, a 0.49 Mb region was mapped to the distal portion of chromosome 19 (Chr19: 55,358,186–55,848,473) with a maximum LOD score of 3.07 (Fig 2A). The identified locus is represented by 41 probe sets. Investigation of the phase and inheritance pattern of the identified haploblock revealed complete concordance of the locus inheritance with the disease phenotype in all affected versus unaffected carriers. Multipoint linkage analysis extended the locus to 1.82 Mbp (Chr19: 54,949,124–56,765,346) and achieved a LOD score of 3.24 (Fig 2B and 2C). This extended locus is represented by 151 probe sets and contains a total of 12 Ensemble-predicted canine genes (Fig 3). A theoretical maximum LOD score was manually calculated for this pedigree and was estimated to be 5.4.


Variants in Nebulin (NEB) Are Linked to the Development of Familial Primary Angle Closure Glaucoma in Basset Hounds.

Ahram DF, Grozdanic SD, Kecova H, Henkes A, Collin RW, Kuehn MH - PLoS ONE (2015)

Graphical representation of two-point and multipoint linkage analysis results.The larger locus identified with using multipoint linkage analysis a maximum LODmultipoint score of 3.24 (Chr19: 54,949,124–56,765,346) brackets the region identified using two-point linkage analysis (Chr19: 55,358,186–55,848,473) and contains a total of 12 Ensemble-predicted canine genes. Comparison of the linked locus to the human genome reveals shared synteny with a region on chromosome 2. The number and order of genes identified within the canine locus are completely conserved in the syntenic human region.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4418656&req=5

pone.0126660.g003: Graphical representation of two-point and multipoint linkage analysis results.The larger locus identified with using multipoint linkage analysis a maximum LODmultipoint score of 3.24 (Chr19: 54,949,124–56,765,346) brackets the region identified using two-point linkage analysis (Chr19: 55,358,186–55,848,473) and contains a total of 12 Ensemble-predicted canine genes. Comparison of the linked locus to the human genome reveals shared synteny with a region on chromosome 2. The number and order of genes identified within the canine locus are completely conserved in the syntenic human region.
Mentions: Using genome-wide, two-point linkage analysis, a 0.49 Mb region was mapped to the distal portion of chromosome 19 (Chr19: 55,358,186–55,848,473) with a maximum LOD score of 3.07 (Fig 2A). The identified locus is represented by 41 probe sets. Investigation of the phase and inheritance pattern of the identified haploblock revealed complete concordance of the locus inheritance with the disease phenotype in all affected versus unaffected carriers. Multipoint linkage analysis extended the locus to 1.82 Mbp (Chr19: 54,949,124–56,765,346) and achieved a LOD score of 3.24 (Fig 2B and 2C). This extended locus is represented by 151 probe sets and contains a total of 12 Ensemble-predicted canine genes (Fig 3). A theoretical maximum LOD score was manually calculated for this pedigree and was estimated to be 5.4.

Bottom Line: Using exome-sequencing analysis, a possibly damaging, non-synonymous variant in the gene Nebulin (NEB) was found to segregate with PACG which alters a phylogenetically conserved Lysine residue.Nebulin, a protein that promotes the contractile function of sarcomeres, was found to be prominently expressed in the ciliary muscles of the anterior segment.The phenotypic similarities of disease presentation in dogs and humans may enable the translation of findings made in this study to patients with PACG.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA, United States of America.

ABSTRACT
Several dog breeds are susceptible to developing primary angle closure glaucoma (PACG), which suggests a genetic basis for the disease. We have identified a four-generation Basset Hound pedigree with characteristic autosomal recessive PACG that closely recapitulates PACG in humans. Our aim is to utilize gene mapping and whole exome sequencing approaches to identify PACG-causing sequence variants in the Basset. Extensive clinical phenotyping of all pedigree members was conducted. SNP-chip genotyping was carried out in 9 affected and 15 unaffected pedigree members. Two-point and multipoint linkage analyses of genome-wide SNP data were performed using Superlink-Online SNP-1.1 and a locus was mapped to chromosome 19q with a maximum LOD score of 3.24. The locus contains 12 Ensemble predicted canine genes and is syntenic to a region on chromosome 2 in the human genome. Using exome-sequencing analysis, a possibly damaging, non-synonymous variant in the gene Nebulin (NEB) was found to segregate with PACG which alters a phylogenetically conserved Lysine residue. The association of this variants with PACG was confirmed in a secondary cohort of unrelated Basset Hounds (p = 3.4 × 10-4, OR = 15.3 for homozygosity). Nebulin, a protein that promotes the contractile function of sarcomeres, was found to be prominently expressed in the ciliary muscles of the anterior segment. Our findings may provide insight into the molecular mechanisms that underlie PACG. The phenotypic similarities of disease presentation in dogs and humans may enable the translation of findings made in this study to patients with PACG.

No MeSH data available.


Related in: MedlinePlus