scholarly journals Progressive rod-cone degeneration (PRCD) in selected dog breeds and variability in its phenotypic expression

2011 ◽  
Vol 56 (No. 5) ◽  
pp. 243-247 ◽  
Author(s):  
J. Dostal ◽  
A. Hrdlicova ◽  
P. Horak
Keyword(s):  
Centromeric Region ◽  
Late Onset ◽  
Phenotypic Expression ◽  
Modifier Gene ◽  
Chromosome 9 ◽  
Causative Mutation ◽  
Photoreceptor Degeneration ◽  
Cocker Spaniel ◽  
Canine Chromosome ◽  
Portuguese Water

Progressive rod-cone degeneration (PRCD) is a late onset autosomal photoreceptor degeneration found in canines. PRCD in canines is homologous to one form of retinitis pigmentosa (RP) found in humans and displays phenotypic similarity as well as having the identical causative mutation. The PRCD gene was mapped to the centromeric region of canine chromosome 9 (CFA9). We report here a population study of 699 dogs of the following breeds and the following frequencies of the disease-causing mutation: American Cocker Spaniel (0.09), English Cocker Spaniel (0.34), English Springer Spaniel (0.00), Welsh Springer Spaniel (0.00), Flat Coated Retriever (0.00), Golden Retriever (0.00), Chesapeake Bay Retriever (0.14), Nova Scotia Duck Tolling Retriever (0.44), Labrador Retriever (0.07), Poodle Toy (0.45), Poodle Miniature (0.20), Poodle Medium (0.05), Poodle Standard (0.00), Portuguese Water Dog (0.33), Chinese Crested Dog (0.02), Shipperke (0.06), and Australian Cattle Dog (0.00). The disease results in complete blindness in the affected individual in almost every case. The time of onset and disease progression varies between dog breeds as well as between individuals. A modifier gene is likely to segregate in genomic proximity to the PRCD gene and may influence phenotypic expression.

scholarly journals Sex differences in the prevalence of genetic mutations in FTD and ALS

Neurology ◽  
2017 ◽  
Vol 89 (15) ◽  
pp. 1633-1642 ◽  
Author(s):  
Ashley F. Curtis ◽  
Mario Masellis ◽  
Ging-Yuek Robin Hsiung ◽  
Rahim Moineddin ◽  
Kathy Zhang ◽  
...  
Keyword(s):  
Sex Differences ◽  
Meta Analysis ◽  
Phenotypic Expression ◽  
Chromosome 9 ◽  
Random Effects Models ◽  
Reading Frame ◽  
Female Patients ◽  
Hexanucleotide Repeat ◽  
Mutation Carriers ◽  
Related Risk

Objective:To conduct a meta-analysis that investigates sex differences in the prevalence of mutations in the 3 most common genes that cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)—chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), or microtubule-associated protein tau (MAPT)—in patients clinically diagnosed with these conditions.Methods:MEDLINE, EMBASE, and PsycINFO databases were searched (inception to June 30, 2016). Studies of patients with FTD or ALS that reported the number of men and women with and without mutations of interest were selected. Female to male pooled risk ratios (RR) and 95% confidence intervals (CI) for each mutation were calculated using random-effects models.Results:Thirty-two articles reporting 12,784 patients with ALS (including 1,244 C9orf72 mutation carriers) revealed a higher prevalence of female patients with C9orf72-related ALS (RR 1.16, 95% CI 1.04–1.29). Twenty-three articles reporting 5,320 patients with FTD (including 488 C9orf72 mutation carriers) revealed no sex differences in C9orf72-related FTD (RR 0.95, 95% CI 0.81–1.12). Thirty-six articles reporting 3,857 patients with FTD (including 369 GRN mutation carriers) revealed a higher prevalence of female patients with GRN-related FTD (RR 1.33, 95% CI 1.09–1.62). Finally, 21 articles reporting 2,377 patients with FTD (including 215 MAPT mutation carriers) revealed no sex difference in MAPT-related FTD (RR 1.21, 95% CI 0.95–1.55).Conclusions:Higher female prevalence of C9orf72 hexanucleotide repeat expansions in ALS and GRN mutations in FTD suggest that sex-related risk factors might moderate C9orf72 and GRN-mediated phenotypic expression.

scholarly journals CCDC66 frameshift variant associated with a new form of early-onset progressive retinal atrophy in Portuguese Water Dogs

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Leonardo Murgiano ◽  
Doreen Becker ◽  
Courtney Spector ◽  
Kendall Carlin ◽  
Evelyn Santana ◽  
...  
Keyword(s):  
Early Onset ◽  
Autosomal Recessive ◽  
Late Onset ◽  
Unrelated Control ◽  
Progressive Retinal Atrophy ◽  
Mutant Transcript ◽  
Retinal Atrophy ◽  
Portuguese Water ◽  
New Form

AbstractAberrant photoreceptor function or morphogenesis leads to blinding retinal degenerative diseases, the majority of which have a genetic aetiology. A variant in PRCD previously identified in Portuguese Water Dogs (PWDs) underlies prcd (progressive rod-cone degeneration), an autosomal recessive progressive retinal atrophy (PRA) with a late onset at 3–6 years of age or older. Herein, we have identified a new form of early-onset PRA (EOPRA) in the same breed. Pedigree analysis suggested an autosomal recessive inheritance. Four PWD full-siblings affected with EOPRA diagnosed at 2–3 years of age were genotyped (173,661 SNPs) along with 2 unaffected siblings, 2 unaffected parents, and 15 unrelated control PWDs. GWAS, linkage analysis and homozygosity mapping defined a 26-Mb candidate region in canine chromosome 20. Whole-genome sequencing in one affected dog and its obligatory carrier parents identified a 1 bp insertion (CFA20:g.33,717,704_33,717,705insT (CanFam3.1); c.2262_c.2263insA) in CCDC66 predicted to cause a frameshift and truncation (p.Val747SerfsTer8). Screening of an extended PWD population confirmed perfect co-segregation of this genetic variant with the disease. Western blot analysis of COS-1 cells transfected with recombinant mutant CCDC66 expression constructs showed the mutant transcript translated into a truncated protein. Furthermore, in vitro studies suggest that the mutant CCDC66 is mislocalized to the nucleus relative to wild type CCDC66. CCDC66 variants have been associated with inherited retinal degenerations (RDs) including canine and murine ciliopathies. As genetic variants affecting the primary cilium can cause ciliopathies in which RD may be either the sole clinical manifestation or part of a syndrome, our findings further support a role for CCDC66 in retinal function and viability, potentially through its ciliary function.

Patching Together the Genetics of Gorlin Syndrome

1998 ◽  
Vol 3 (1) ◽  
pp. 31-34 ◽  
Author(s):  
Sherri J. Bale ◽  
Roni T. Falk ◽  
Geraldine R. Rogers
Keyword(s):  
Loss Of Heterozygosity ◽  
Genetic Basis ◽  
Clinical Presentation ◽  
Phenotypic Expression ◽  
Chromosome 9 ◽  
Gorlin Syndrome ◽  
Autosomal Dominant Disorder ◽  
Developmental Defects ◽  
Standard Family ◽  
Basal Cell Carcinomas

Background: Gorlin syndrome is an autosomal dominant disorder characterized by developmental defects and susceptibility to cancer, especially to basal cell carcinomas. The genetic basis of this disorder has recently been elucidated. Methods: In this article previous studies are reviewed in which loss of heterozygosity analysis of tumours and normal tissue pointed to a region on chromosome 9 as being involved in Gorlin syndrome. In this light, Knudson's two-hit model is discussed. The identification of the involvement of the patched gene in Gorlin syndrome is reviewed. New data on genotype-phenotype correlations in the syndrome are presented. Results: Loss-of-heterozygosity studies, together with standard family studies using linkage analysis, have proved useful in identifying the location of a gene with complex phenotypic expression. Conclusion: The application of the two-hit model, as utilized in loss-of-heterozygosity studies, has been very useful in elucidating the genetic basis of Gorlin syndrome. There may be a correlation between certain aspects of the mutations in patched and the clinical presentation of the disorder in families.

scholarly journals Natural selection increases mutational robustness in complex diseases: Mendelian evidence from early versus late onset common diseases

2013 ◽  
Author(s):  
Bora E Baysal
Keyword(s):  
Natural Selection ◽  
Early Onset ◽  
Late Onset ◽  
Disease Onset ◽  
Phenotypic Expression ◽  
Complex Diseases ◽  
World Health ◽  
Common Disease ◽  
Common Diseases ◽  
Age Related

Background. Natural selection operates on genetically influenced phenotypic variations that confer differential survival or reproductive advantages. Common diseases are frequently associated with increased mortality and disability and complex heritable factors play an important role in their pathogenesis. Hence, common diseases should trigger the process of natural selection with subsequent population genetic response. However, empirical impact of natural selection on genetics of complex diseases is poorly understood. In this paper, I hypothesize that negative selection of diseased individuals leads to systemic genetic differences between common diseases that primarily occur before or during the reproductive years (early onset) and those that occur after the reproductive years (late onset). Methods. To test this hypothesis, a comprehensive literature survey of highly penetrant (80% or more) nonpleiotropic, nonsyndromic susceptibility genes (hereafter defined as Mendelian phenocopies) was completed for early versus late onset common diseases, organized using the World Health Organization (WHO) ICD-10 classification scheme. An average age at sporadic disease onset of 30 years was selected for dividing early versus late onset common diseases. Results. Mendelian phenocopies were identified for 16 primarily late onset common diseases from 9 distinct WHO diagnostic categories. Late onset common diseases with Mendelian phenocopies include papillary renal carcinoma, obesity, Alzheimer disease, Parkinson disease, frontotemporal dementia, amyotrophic lateral sclerosis, primary open angle glaucoma, age-related hearing loss, coronary artery disease, stroke, pancreatitis, thrombotic thrombocytopenic purpura, systemic lupus erythematosus, inclusion body myositis, Paget's disease of bone and focal segmental glomerulosclerosis (steroid resistant). In contrast, no Mendelian phenocopy was found for any primarily early onset common disease (p<5.8x10-4). Thus, highly predictive rare variants are present for a subset of late onset common diseases, but not for early onset common diseases. Discussion. These findings suggest that genetic architecture of early onset common diseases is more robust against the phenotypic expression of highly penetrant predisposing mutations than is the case for late onset common diseases. The primary candidate for increased genetic robustness in early onset common diseases is proposed to be natural selection.

scholarly journals Distinct genetic regions modify specific muscle groups in muscular dystrophy

2011 ◽  
Vol 43 (1) ◽  
pp. 24-31 ◽  
Author(s):  
Kayleigh A. Swaggart ◽  
Ahlke Heydemann ◽  
Abraham A. Palmer ◽  
Elizabeth M. McNally
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Membrane Permeability ◽  
Single Gene ◽  
Genetic Modifier ◽  
Phenotypic Expression ◽  
Chromosome 9 ◽  
Mouse Strains ◽  
Abdominal Muscles ◽  
Muscle Groups

Phenotypic expression in the muscular dystrophies is variable, even with the identical mutation, providing strong evidence that genetic modifiers influence outcome. To identify genetic modifier loci, we used quantitative trait locus mapping in two differentially affected mouse strains with muscular dystrophy. Using the Sgcg model of limb girdle muscular dystrophy that lacks the dystrophin-associated protein γ-sarcoglycan, we evaluated chromosomal regions that segregated with two distinct quantifiable characteristics of muscular dystrophy, membrane permeability and fibrosis. We previously identified a single major locus on murine chromosome 7 that influences both traits of membrane permeability and fibrosis in the quadriceps muscle. Using a larger cohort, we now found that this same interval strongly associated with both traits in all limb skeletal muscle groups studied, including the gastrocnemius/soleus, gluteus/hamstring, and triceps muscles. In contrast, the muscles of the trunk were modified by distinct genetic loci, possibly reflecting the embryological origins and physiological stressors unique to these muscle groups. A locus on chromosome 18 was identified that modified membrane permeability of the abdominal muscles, and a locus on chromosome 3 was found that regulated diaphragm and abdominal muscle fibrosis. Fibrosis in the heart associated with a region on chromosome 9 and likely reflects differential function between cardiac and skeletal muscle. These data underscore the complexity of inheritance and penetrance of single-gene disorders.

scholarly journals A Human Mitochondrial GTP Binding Protein Related to tRNA Modification May Modulate Phenotypic Expression of the Deafness-Associated Mitochondrial 12S rRNA Mutation

2002 ◽  
Vol 22 (21) ◽  
pp. 7701-7711 ◽  
Author(s):  
Xiaoming Li ◽  
Min-Xin Guan
Keyword(s):  
Binding Protein ◽  
Phenotypic Expression ◽  
Modifier Gene ◽  
12S Rrna ◽  
Trna Modification ◽  
Gtp Binding Protein ◽  
A1555g Mutation ◽  
Gtp Binding ◽  
Mitochondrial 12S Rrna ◽  
Respiratory Deficient

ABSTRACT Human mitochondrial 12S rRNA A1555G mutation has been found to be associated with deafness. However, putative nuclear modifier gene(s) has been proposed to regulate the phenotypic expression of this mutation. In yeast cells, mutant alleles of MSS1, encoding a mitochondrial GTP-binding protein, manifest a respiratory-deficient phenotype only when coupled with mitochondrial 15S rRNA PR 454 mutation corresponding to human A1555G mutation. This suggests that an MSS1-like modifier gene may influence the phenotypic expression of the A1555G mutation. We report here the identification and characterization of human MSS1 homolog, GTPBP3, the first identified vertebrate gene related to mitochondrial tRNA modification. The Gtpbp3 is the mitochondrial GTPase evolutionarily conserved from bacteria to mammals. Functional conservation of this protein is supported by the observation that isolated human GTPBP3 cDNA can complement the respiratory-deficient phenotype of yeast mss1 cells carrying PR 454 mutation. GTPBP3 is ubiquitously expressed in various tissues as multiple transcripts, but with a markedly elevated expression in tissues of high metabolic rates. We showed that Gtpbp3 localizes in mitochondrion. These observations suggest that the human GTPBP3 is a structural and functional homolog of yeast MSS1. Thus, allelic variants in GTPBP3 could, if they exist, modulate the phenotypic manifestation of human mitochondrial A1555G mutation.

Sign in / Sign up

Export Citation Format

Share Document