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.

Early-Onset, Autosomal Recessive, Progressive Retinal Atrophy in Persian Cats

2005 ◽  
Vol 46 (5) ◽  
pp. 1742 ◽  
Author(s):  
HyungChul Rah ◽  
David J. Maggs ◽  
Thomas N. Blankenship ◽  
Kristina Narfstrom ◽  
Leslie A. Lyons
Keyword(s):  
Early Onset ◽  
Autosomal Recessive ◽  
Progressive Retinal Atrophy ◽  
Retinal Atrophy

scholarly journals Altered Proteolysis in Fibroblasts of Alzheimer Patients with Predictive Implications for Subjects at Risk of Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Alessandra Mocali ◽  
Nunzia Della Malva ◽  
Claudia Abete ◽  
Vito Antonio Mitidieri Costanza ◽  
Antonio Bavazzano ◽  
...  
Keyword(s):  
Early Onset ◽  
Age Of Onset ◽  
Late Onset ◽  
Low Cost ◽  
Apoe Genotype ◽  
Normal Subjects ◽  
Culture Conditions ◽  
Cultured Fibroblasts ◽  
Laboratory Tool

There is great interest in developing reliable biomarkers to support antemortem diagnosis of late-onset Alzheimer’s disease (AD). Early prediction and diagnosis of AD might be improved by the detection of a proteolytic dysfunction in extracts from cultured AD fibroblasts, producing altered isoelectrophoretic forms of the enzyme transketolase (TK-alkaline bands). The TK profile and apolipoprotein E (APOE) genotype were examined in fibroblasts from 36 clinically diagnosed probable late-onset sporadic AD patients and 38 of their asymptomatic relatives, 29 elderly healthy individuals, 12 neurological non-AD patients, and 5 early-onset AD patients. TK alterations occurred in (i) several probable AD patients regardless of age-of-onset and severity of disease; (ii) all early-onset AD patients and APOEε4/4 carriers; and (iii) nearly half of asymptomatic AD relatives. Normal subjects and non-AD patients were all negative. Notably, culture conditions promoting TK alterations were also effective in increasing active BACE1 levels. Overall, the TK assay might represent a low-cost laboratory tool useful for supporting AD differential diagnosis and identifying asymptomatic subjects who are at greater risk of AD and who should enter a follow-up study. Moreover, the cultured fibroblasts were confirmed as a usefulin vitromodel for further studies on the pathogenetic process of AD.

scholarly journals Early-Onset Progressive Retinal Atrophy Associated with an IQCB1 Variant in African Black-Footed Cats (Felis nigripes)

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Annie Oh ◽  
◽  
Jacqueline W. Pearce ◽  
Barbara Gandolfi ◽  
Erica K. Creighton ◽  
...  
Keyword(s):  
Early Onset ◽  
Vision Loss ◽  
Binding Motif ◽  
Progressive Retinal Atrophy ◽  
Calmodulin Binding ◽  
Species Survival ◽  
Retinal Atrophy ◽  
African Black ◽  
Vision Deficits ◽  
Variant Database

Abstract African black-footed cats (Felis nigripes) are endangered wild felids. One male and full-sibling female African black-footed cat developed vision deficits and mydriasis as early as 3 months of age. The diagnosis of early-onset progressive retinal atrophy (PRA) was supported by reduced direct and consensual pupillary light reflexes, phenotypic presence of retinal degeneration, and a non-recordable electroretinogram with negligible amplitudes in both eyes. Whole genome sequencing, conducted on two unaffected parents and one affected offspring was compared to a variant database from 51 domestic cats and a Pallas cat, revealed 50 candidate variants that segregated concordantly with the PRA phenotype. Testing in additional affected cats confirmed that cats homozygous for a 2 base pair (bp) deletion within IQ calmodulin-binding motif-containing protein-1 (IQCB1), the gene that encodes for nephrocystin-5 (NPHP5), had vision loss. The variant segregated concordantly in other related individuals within the pedigree supporting the identification of a recessively inherited early-onset feline PRA. Analysis of the black-footed cat studbook suggests additional captive cats are at risk. Genetic testing for IQCB1 and avoidance of matings between carriers should be added to the species survival plan for captive management.

A novel mutation in PDE6B in Spanish Water Dogs with early‐onset progressive retinal atrophy

2020 ◽  
Vol 23 (5) ◽  
pp. 792-796
Author(s):  
Paige A. Winkler ◽  
Harrison D. Ramsey ◽  
Simon M. Petersen‐Jones
Keyword(s):  
Early Onset ◽  
Novel Mutation ◽  
Progressive Retinal Atrophy ◽  
Retinal Atrophy

scholarly journals Single Point Mutation from E22-to-K in Aβ Initiates Early-Onset Alzheimer’s Disease by Binding with Catalase

2020 ◽  
Vol 2020 ◽  
pp. 1-21
Author(s):  
Wenjing Jiang ◽  
YanYu ◽  
Dandan Yao ◽  
Xuechao Fei ◽  
Li Ai ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Point Mutation ◽  
Early Onset ◽  
Late Onset ◽  
Single Point ◽  
Single Point Mutation ◽  
Neuron Death ◽  
Mutation Site

Amyloid-beta (Aβ) is a critical etiological factor for late-onset familial Alzheimer’s disease (AD). However, an early-onset AD has been found to be related with an Aβ mutation in glutamic acid 22-to-lysine (Italian type E22K). Why only one single point mutation at E22 residue induces AD remains unclear. Here, we report that a Chinese familial AD pedigree with E22K mutation was associated with higher levels of serum hydrogen peroxide (H2O2) and lower activity of catalase (a H2O2 degrading enzyme) than controls. Further, we found that E22K binding with catalase caused more severe H2O2 accumulation in the brains of E22K-injected rats than Aβ-injected rats. Unexpectedly, H2O2 bound with the mutation site 22K residue of E22K and elicited more rapid aggregation of E22K than Aβ in vitro. Moreover, H2O2 acted with E22K synergistically to induce higher cellular toxicity than with Aβ. Notably, intrahippocampal infusion of E22K led to more severe plaque deposition, neuron death, and more rapid memory decline than Aβ-injected rats. However, L-cysteine, a H2O2 scavenger, not only prevented self-aggregation of E22K but also reduced H2O2-promoted E22K assembly in vitro; subsequently, it alleviated Alzheimer-related phenotypes. Hence, E22K binding with catalase promotes the early onset of familial AD, and L-cys may reverse this disease.

Late-onset progressive retinal atrophy in the Gordon and Irish Setter breeds is associated with a frameshift mutation inC2orf71

2012 ◽  
Vol 44 (2) ◽  
pp. 169-177 ◽  
Author(s):  
L. M. Downs ◽  
J. S. Bell ◽  
J. Freeman ◽  
C. Hartley ◽  
L. J. Hayward ◽  
...  
Keyword(s):  
Frameshift Mutation ◽  
Late Onset ◽  
Progressive Retinal Atrophy ◽  
Retinal Atrophy

ABCA4-Associated Stargardt Disease

2020 ◽  
Vol 237 (03) ◽  
pp. 267-274 ◽  
Author(s):  
Mubeen Khan ◽  
Frans P.M. Cremers
Keyword(s):  
Autosomal Recessive ◽  
Late Onset ◽  
Human Kidney ◽  
In Vitro Assays ◽  
Kidney Cells ◽  
Stargardt Disease ◽  
Abca4 Gene ◽  
Transcriptomics Data ◽  
Degree Of Severity

AbstractAutosomal recessive Stargardt disease (STGD1) is associated with variants in the ABCA4 gene. The phenotypes range from early-onset STGD1, that clinically resembles severe cone-rod dystrophy, to intermediate STGD1 and late-onset STGD1. These different phenotypes can be correlated with different combinations of ABCA4 variants which can be classified according to their degree of severity. A significant fraction of STGD1 cases, particularly late-onset STGD1 cases, were shown to carry only a single ABCA4 variant. A frequent coding variant (p.Asn1868Ile) was recently identified which – in combination with a severe ABCA4 variant – is generally associated with late-onset STGD1. In addition, an increasing number of rare deep-intronic variants have been found and some of these are also associated with late-onset STGD1. The effect of these and other variants on ABCA4 RNA was tested using in vitro assays in human kidney cells using specially designed midigenes. With stem cells and photoreceptor progenitor cells derived from patient skin or blood cells, retina-specific splice defects can be assessed. With expert clinical examination to distinguish STGD1 cases from other maculopathies, as well as in-depth genomics and transcriptomics data, it is now possible to identify both mutant ABCA4 alleles in > 95% of cases.

scholarly journals Erratum: Corrigendum: Early-Onset Progressive Retinal Atrophy Associated with an IQCB1 Variant in African Black-Footed Cats (Felis nigripes)

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Annie Oh ◽  
◽  
Jacqueline W. Pearce ◽  
Barbara Gandolfi ◽  
Erica K. Creighton ◽  
...  
Keyword(s):  
Early Onset ◽  
Progressive Retinal Atrophy ◽  
Retinal Atrophy ◽  
African Black

NEONATAL SEPSIS AND IDENTIFICATION OF RISK FACTORS: STUDY IN AVBRH HOSPITAL SAWANGI

2019 ◽  
Vol 3 (6) ◽  
Author(s):  
Pramod P. Singhavi
Keyword(s):  
Risk Factors ◽  
Neonatal Sepsis ◽  
Early Onset ◽  
Late Onset ◽  
Signs And Symptoms ◽  
Premature Rupture ◽  
Maternal Risk ◽  
Late Onset Sepsis ◽  
Early Onset Sepsis ◽  
Meconium Stained Amniotic Fluid

Introduction: India has the highest incidence of clinical sepsis i.e.17,000/ 1,00,000 live births. In Neonatal sepsis septicaemia, pneumonia, meningitis, osteomyelitis, arthritis and urinary tract infections can be included. Mortality in the neonatal period each year account for 41% (3.6 million) of all deaths in children under 5 years and most of these deaths occur in low income countries and about one million of these deaths are due to infectious causes including neonatal sepsis, meningitis, and pneumonia. In early onset neonatal sepsis (EOS) Clinical features are non-specific and are inefficient for identifying neonates with early-onset sepsis. Culture results take up to 48 hours and may give false-positive or low-yield results because of the antenatal antibiotic exposure. Reviews of risk factors has been used globally to guide the development of management guidelines for neonatal sepsis, and it is similarly recommended that such evidence be used to inform guideline development for management of neonatal sepsis. Material and Methods: This study was carried out using institution based cross section study . The total number neonates admitted in the hospital in given study period was 644, of which 234 were diagnosed for neonatal sepsis by the treating pediatrician based on the signs and symptoms during admission. The data was collected: Sociodemographic characteristics; maternal information; and neonatal information for neonatal sepsis like neonatal age on admission, sex, gestational age, birth weight, crying immediately at birth, and resuscitation at birth. Results: Out of 644 neonates admitted 234 (36.34%) were diagnosed for neonatal sepsis by the paediatrician based on the signs and symptoms during admission. Of the 234 neonates, 189 (80.77%) infants were in the age range of 0 to 7 days (Early onset sepsis) while 45 (19.23%) were aged between 8 and 28 days (Late onset sepsis). Male to female ratio in our study was 53.8% and 46% respectively. Out of total 126 male neonates 91(72.2%) were having early onset sepsis while 35 (27.8%) were late onset type. Out of total 108 female neonates 89(82.4%) were having early onset sepsis while 19 (17.6%) were late onset type. Maternal risk factors were identified in 103(57.2%) of early onset sepsis cases while in late onset sepsis cases were 11(20.4%). Foul smelling liquor in early onset sepsis and in late onset sepsis was 10(5.56%) and 2 (3.70%) respectively. In early onset sepsis cases maternal UTI, Meconium stained amniotic fluid, Multipara and Premature rupture of membrane was seen in 21(11.67%), 19 (10.56%), 20(11.11%) and 33 (18.33%) cases respectively. In late onset sepsis cases maternal UTI, Meconium stained amniotic fluid, Multipara and Premature rupture of membrane was seen in 2 (3.70%), 1(1.85%), 3 (5.56%) and 3 (5.56%) cases respectively. Conclusion: Maternal risk identification may help in the early identification and empirical antibiotic treatment in neonatal sepsis and thus mortality and morbidity can be reduced.

CANVAS is a common form of late-onset hereditary ataxia

2020 ◽  
pp. 51-52
Author(s):  
Е.П. Нужный ◽  
Н.Ю. Абрамычева ◽  
Е.Г. Воробьева ◽  
Е.О. Иванова ◽  
Ю.А. Шпилюкова ◽  
...  
Keyword(s):  
Cerebellar Ataxia ◽  
Clinical Picture ◽  
Autosomal Recessive ◽  
Late Onset ◽  
Repeat Expansion ◽  
Hereditary Ataxia ◽  
Recessive Ataxia ◽  
Autosomal Recessive Ataxia

Синдром CANVAS (мозжечковая атаксия, невропатия и вестибулярная арефлексия) - аутосомно-рецессивная атаксия с поздним дебютом, обусловленная носительством биаллельной экспансии (AAGGG)n во 2-м интроне гена RFC1. До настоящего момента отсутствуют сведения о распространенности данного заболевания в российских семьях. Нами был проведен поиск биаллельной экспансии AAGGG-повторов у 35 российских пациентов с поздней мозжечковой атаксией. Верифицированы 5 пациентов (14,3%) с синдромом CANVAS и характерной клинической картиной. CANVAS (cerebellar ataxia, neuropathy and vestibular areflexia) is a late-onset autosomal recessive ataxia due to biallelic (AAGGG)n repeat expansion in the 2nd intron of the RFC1 gene. There is no information on the CANVAS prevalence in Russian families. We searched for biallelic expansion of AAGGG repeats in 35 Russian patients with late-onset cerebellar ataxia. Five patients (14.3%) with CANVAS syndrome and a characteristic clinical picture were verified.

Sign in / Sign up

Export Citation Format

Share Document