Inheritance of proportionate dwarfism in Angus cattle

Objective To determine the mode of inheritance of congenital proportionate dwarfism in Angus and Angus crossbred cattle, initially detected in two commercial beef herds in northern New South Wales. Design Matings of normal carrier sires to unrelated cows of diverse breeds, and of one carrier sire to his unaffected daughters. An unrelated Piedmontese bull was also mated to unaffected daughters of the carrier sires. Procedure Two carrier Angus bulls and nine unaffected daughters, all of whom were completely indistinguishable from normal animals, were purchased for controlled breeding studies under known nutritional and disease conditions. Affected and carrier individuals were examined for the presence of obvious chromosomal abnormalities. Results Angus dwarfism has been successfully reproduced under controlled experimental conditions over successive years using unrelated dams and is undoubtedly heritable. The high frequency of occurrence of affected individuals (23/61 = 0.38 +/- .06) among the progeny of matings of the Angus sires to unrelated females of diverse breeding is not compatible with recessive inheritance, because of the negligible frequency of proportionate dwarfism in the breeds of the dams. Both paternal and maternal transmission of the defect was demonstrated, so that imprinting in the strict sense of a gene that is only expressed when received from the male parent appears not to be involved. Tested individuals showed no evidence of gross chromosomal abnormality. Dominant autosomal inheritance with incomplete penetrance was indicated by the lack of expression of the defective gene in the two Angus sires and in three unaffected daughters who produced dwarf calves from matings to the Piedmontese bull. Conclusions The mode of inheritance is that of a single autosomal dominant gene with a penetrance coefficient of 0.75 +/- 0.12, estimated from the observed incidence of 23/61 affected offspring of the two carrier Angus bulls mated to unrelated dams. Simple genetic models involving either (i) an unstable mutant which changes at high frequency to the expressed dominant dwarfing allele during gametogenesis, or (ii) a dominant allele with penetrance determined by an unlinked modifying locus, are shown to be compatible with the experimental data. Both models indicate that penetrance of the dwarfing gene may possibly be higher in matings involving carrier daughters of the two Angus bulls.

Identification of a novel frameshift mutation in the giant muscle filament titin in a large Australian family with dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is an etiologically heterogeneous cardiac disease characterized by left ventricular dilation and systolic dysfunction. Approximately 25-30% of DCM patients show a family history of mainly autosomal dominant inheritance. We and others have previously demonstrated that mutations in the giant muscle filament titin (TTN) can cause DCM. However, the prevalence of titin mutations in familial DCM is unknown. In this paper, we report a novel heterozygous 1-bp deletion mutation (c.62890delG) in TTN that cosegregates with DCM in a large Australian pedigree (A3). The TTN deletion mutation c.62890delG causes a frameshift, thereby generating a truncated A-band titin due to a premature stop codon (p.E20963KfsX10) and the addition of ten novel amino acid residues. The clinical phenotype of DCM in kindred A3 demonstrates incomplete penetrance and variable expressivity. Finally, protein analysis of a skeletal muscle biopsy sample from an affected member did not reveal the predicted truncated titin isoform although the aberrant mRNA was present, suggesting posttranslational modification and degradation of the truncated protein. The identification of a novel disease-causing mutation in the giant titin gene in a third large family with DCM indicates that mutations in titin may account for a significant portion of the genetic etiology in familial DCM.

Ectopic calcification in the Azores - Clinical and radiological manifestations of Diffuse Idiopathic Skeletal Hypertosis and Chondrocalcinosis families

Objective. Twelve families that were multiply affected with diffuse idiopathic skeletal hyperostosis (DISH) and/or chondrocalcinosis, were identified on the island of Terceira, The Azores, potentially supporting the hypothesis that the 2 disorders share common etiopathogenic factors. The present study was undertaken to investigate this hypothesis. Methods. One hundred three individuals from 12 unrelated families were assessed. Probands were identified from patients attending the Rheumatic Diseases Clinic, Hospital de Santo Espirito, in The Azores. Family members were assessed by rheumatologists and radiologists. Radiographs of all family members were obtained, including radiographs of the dorsolumbar spine, pelvis, knees, elbows, and wrists, and all cases were screened for known features of chondrocalcinosis. Results. Ectopic calcifications were identified in 70 patients. The most frequent symptoms or findings were as follows: axial pain, elbow, knee and metacarpophalangeal (MCP) joint pain, swelling, and/or deformity, and radiographic enthesopathic changes. Elbow and MCP joint periarticular calcifications were observed in 35 and 5 patients, respectively, and chondrocalcinosis was identified in 12 patients. Fifteen patients had sacroiliac disease (ankylosis or sclerosis) on computed tomography scans. Fifty-two patients could be classified as having definite (17%), probable (26%), or possible (31%) DISH. Concomitant DISH and chondrocalcinosis was diagnosed in 12 patients. Pyrophosphate crystals were identified from knee effusions in 13 patients. The pattern of disease transmission was compatible with an autosomal-dominant monogenic disease. The mean age at which symptoms developed was 38 years. Conclusion. These families may represent a familial type of pyrophosphate arthropathy with a phenotype that includes peripheral and axial enthesopathic calcifications. The concurrence of DISH and chondrocalcinosis suggests a shared pathogenic mechanism in the 2 conditions.

The relationship between high-sensitivity CRP and polyclonal Free Light Chains as markers of inflammation in chronic disease

Introduction: Serum concentrations of polyclonal free light chains (FLC) represent the activity of the adaptive immune system. This study assessed the relationship between polyclonal FLC and the established marker of innate immunity, C-reactive protein (CRP), in chronic and acute disease. Methods: We utilized four cross-sectional chronic disease patient cohorts: chronic kidney disease (CKD), diabetes, vasculitis and kidney transplantation; and a longitudinal intensive care case series to assess the kinetics of production in acute disease. Results: There was a weak association between polyclonal FLC and high-sensitivity CRP (hs-CRP) in the study cohorts. A longitudinal assessment in acute disease showed a gradual increase in FLC concentrations over time, often when CRP levels were falling, demonstrating clear differences in the response kinetics of CRP and FLC in this setting. Conclusion: Polyclonal FLC and hs-CRP provide independent information as to inflammatory status. Prospective studies are now required to assess the utility of hs-CRP and polyclonal FLC in combination for risk stratification in disease populations. © 2013 John Wiley & Sons Ltd.

Ankyrin is the major oxidised protein in erythrocyte membranes from end-stage renal disease patients on chronic haemodialysis and oxidation is decreased by dialysis and vitamin C supplementation

Chronically haemodialysed end-stage renal disease patients are at high risk of morbidity arising from complications of dialysis, the underlying pathology that has led to renal disease and the complex pathology of chronic kidney disease. Anaemia is commonplace and its origins are multifactorial, involving reduced renal erythropoietin production, accumulation of uremic toxins and an increase in erythrocyte fragility. Oxidative damage is a common risk factor in renal disease and its co-morbidities and is known to cause erythrocyte fragility. Therefore, we have investigated the hypothesis that specific erythrocyte membrane proteins are more oxidised in end-stage renal disease patients and that vitamin C supplementation can ameliorate membrane protein oxidation. Eleven patients and 15 control subjects were recruited to the study. Patients were supplemented with 2 × 500 mg vitamin C per day for 4 weeks. Erythrocyte membrane proteins were prepared pre- and post-vitamin C supplementation for determination of protein oxidation. Total protein carbonyls were reduced by vitamin C supplementation but not by dialysis when investigated by enzyme linked immunosorbent assay. Using a western blot to detect oxidised proteins, one protein band, later identified as containing ankyrin, was found to be oxidised in patients but not controls and was reduced significantly by 60% in all patients after dialysis and by 20% after vitamin C treatment pre-dialysis. Ankyrin oxidation analysis may be useful in a stratified medicines approach as a possible marker to identify requirements for intervention in dialysis patients.

Toward targeted treatments in tuberous sclerosis

Introduction. Tuberous Sclerosis Complex (TSC) is an autosomal-dominant disease caused by the loss of function of the heterodimeric complex hamartin/tuberin due to TSC1/TSC2 gene mutation. The consequent abnormal activation of mammalian target of rapamycin (mTOR), a serine threonine kinase regulating cellular growth, metabolism and proliferation, is responsible for the structural and functional abnormalities observed in TSC. mTOR inhibitors are a class of drugs specifically targeting the mTOR pathway with promising benefits as a specific targeted treatment of the disease. Areas covered. We have reviewed the literature focusing on the role of mTOR inhibitors in treating TSC-related conditions. They are currently approved for subependymal giant cell astrocytomas, renal angiomyolipomas and more recently for lymphangioleiomyomatosis, but a promising role has been shown also in the other clinical manifestation characteristics of TSC, such as cardiac rhabdomyomas, facial angiofibromas and epilepsy. Expert opinion. mTOR inhibition is considered a disease-modifying therapy and the best approach to prevent the progress of the natural history of the disease. For the first time we have the possibility not only to use a biologically targeted treatment, but also to address different manifestations at the same time, thus significantly improving the therapeutic outlook in this complex disease.

Risk factors of coronary heart disease and correlates of type 2 diabetes among Cuban Americans

Cuban Americans, a minority Hispanic subgroup, have a high prevalence of type 2 diabetes. Persons with diabetes experience a higher rate of coronary heart disease (CHD) compared to those without diabetes. The objectives of the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) are to investigate the risk factors of CHD and the etiology of diabetes among diabetics of minority ethnic populations. No information is available on the etiology of CHD risks for Cuban Americans. ^ This cross-sectional study compared Cuban Americans with (N = 79) and without (N = 80) type 2 diabetes residing in South Florida. Data on risk factors of CHD and type 2 diabetes were collected using sociodemographics, smoking habit, Rose Angina, Modifiable Activity, and Willet's food frequency questionnaires. Anthropometrics and blood pressure (BP) were recorded. Glucose, glycated hemoglobin, lipid profile, homocysteine, and C-reactive protein were assessed in fasting blood. ^ Diabetics reported a significantly higher rate of angina symptoms than non-diabetics (P = 0.008). After adjusting for age and gender, diabetics had significantly (P < 0.001) larger waist circumference and higher systolic BP than non-diabetics. There was no significant difference in major nutrient intakes between the groups. One quarter of subjects, both diabetics and non-diabetics, exceeded the intake of percent calories from total fat and almost 60% had cholesterol intake >200 mg/d and more than 60% had fiber intake <20 gm/d. The pattern of physical activity did not differ between groups though, it was much below the recommended level. After adjusting for age and gender, diabetics had significantly (P < 0.001) higher levels of blood glucose, glycated hemoglobin, triglycerides, and homocysteine than non-diabetics. In contrast, diabetics had significantly (P < 0.01) lower levels of high-density lipoprotein cholesterol (HDL-C). ^ Multivariate logistic regression analyses showed that increasing age, male gender, large waist circumference, lack of acculturation, and high levels of triglycerides were independent risk factors of type 2 diabetes. In contrast, moderate alcohol consumption conferred protection against diabetes. ^ The study identified several risk factors of CHD and diabetes among Cuban Americans. Health care providers are encouraged to practice ethno-specific preventive measures to lower the burden of CHD and diabetes in Cuban Americans. ^

Long term effects of gestational hypertension and pre-eclampsia on kidney function : Record linkage study

This research was funded by the Chief Scientists Office, Scotland (CZH/4/659).

Identification des gènes modifiant l’âge d’apparition du glaucome primaire à angle-ouvert dans une famille canadienne-française fondatrice.

Le glaucome est un groupe hétérogène de maladies qui sont caractérisées par l’apoptose des cellules ganglionnaires de la rétine et la dégénérescence progressive du nerf optique. Il s’agit de la première cause de cécité irréversible, qui touche environ 60 millions de personnes dans le monde. Sa forme la plus commune est le glaucome à angle ouvert (GAO), un trouble polygénique causé principalement par une prédisposition génétique, en interaction avec d’autres facteurs de risque tels que l’âge et la pression intraoculaire élevée (PIO). Le GAO est une maladie génétique complexe, bien que certaines formes sévères sont autosomiques dominantes. Dix-sept loci ont été liés à la maladie et acceptés par la « Human Genome Organisation » (HUGO) et cinq gènes ont été identifiés à ces loci (MYOC, OPTN, WDR36, NTF4, ASB10). Récemment, des études d’association sur l’ensemble du génome ont identifié plus de 20 facteurs de risque fréquents, avec des effets relativement faibles. Depuis plus de 50 ans, notre équipe étudie 749 membres de la grande famille canadienne-française CA où la mutation MYOCK423E cause une forme autosomale dominante de GAO dont l’âge de début est fortement variable. Premièrement, il a été montré que cette variabilité de l’âge de début de l’hypertension intraoculaire possède une importante composante génétique causée par au moins un gène modificateur. Ce modificateur interagit avec la mutation primaire et altère la sévérité du glaucome chez les porteurs de MYOCK423E. Un gène modificateur candidat WDR36 a été génotypé dans 2 grandes familles CA et BV. Les porteurs de variations non-synonymes de WDR36 ainsi que de MYOCK423E de la famille CA ont montré une tendance à développer la maladie plus jeune. Un outil de forage de données a été développé pour représenter des informations connues relatives à la maladie et faciliter la priorisation des gènes candidats. Cet outil a été appliqué avec succès à la dépression bipolaire et au glaucome. La suite du projet consiste à finaliser un balayage de génome sur la famille CA et à séquencer les loci afin d’identifier les variations modificatrices du glaucome. Éventuellement, ces variations permettront d’identifier les individus dont le glaucome risque d’être plus agressif.

Trans-ethnic fine mapping highlights kidney-function genes linked to salt sensitivity

We analyzed genome-wide association studies (GWASs), including data from 71,638 individuals from four ancestries, for estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We identified 20 loci attaining genome-wide-significant evidence of association (p < 5 × 10(-8)) with kidney function and highlighted that allelic effects on eGFR at lead SNPs are homogeneous across ancestries. We leveraged differences in the pattern of linkage disequilibrium between diverse populations to fine-map the 20 loci through construction of "credible sets" of variants driving eGFR association signals. Credible variants at the 20 eGFR loci were enriched for DNase I hypersensitivity sites (DHSs) in human kidney cells. DHS credible variants were expression quantitative trait loci for NFATC1 and RGS14 (at the SLC34A1 locus) in multiple tissues. Loss-of-function mutations in ancestral orthologs of both genes in Drosophila melanogaster were associated with altered sensitivity to salt stress. Renal mRNA expression of Nfatc1 and Rgs14 in a salt-sensitive mouse model was also reduced after exposure to a high-salt diet or induced CKD. Our study (1) demonstrates the utility of trans-ethnic fine mapping through integration of GWASs involving diverse populations with genomic annotation from relevant tissues to define molecular mechanisms by which association signals exert their effect and (2) suggests that salt sensitivity might be an important marker for biological processes that affect kidney function and CKD in humans.

Familial amyloid polyneuropathy: TTR sequencing and "in silico" analysis

Familial amyloid polyneuropathy (FAP) or paramiloidosis is an autosomal dominant neurodegenerative disease with onset on adult age that is characterized by mutated protein deposition in the form of amyloid substance. FAP is due to a point alteration in the transthyretin (TTR) gene and until now more than 100 amyloidogenic mutations have been described in TTR gene. FAP shows a wide variation in age-at-onset (AO) (19-82 years, in Portuguese cases) and the V30M mutation often runs through several generation of asymptomatic carriers, before expressing in a proband, but the protective effect disappear in a single generation, with offspring of late-onset cases having early onset. V30M mutation does not explain alone the symptoms and AO variability of the disease observed in the same family. Our aim in this study was to identify genetic factors associated with AO variability and reduced penetrance which can have important clinical implications. To accomplish this we genotyped 230 individuals, using a directautomated sequencing approach in order to identify possible genetic modifiers within the TTR locus. After genotyping, we assessed a putative association of the SNPs found with AO and an intensive in silico analysis was performed in order to understand a possible regulation of gene expression. Although we did not find any significant association between SNPs and AO, we found very interesting and unreported results in the in silico analysis since we observed some alterations in the mechanism of splicing, transcription factors binding and miRNAs binding. All of these mechanisms when altered can lead to dysregulation of gene expression, which can have an impact in AO and phenotypic variability. These putative mechanisms of regulation of gene expression within the TTR gene could be used in the future as potential therapeutical targets, and could improve genetic counselling and follow-up of mutation carriers.

Management and follow-up of a patient with Familial Atypical Multiple Mole-Melanoma (FAMMM) Syndrome

Introduction. Familial Atypical Multiple Mole-Melanoma Syndrome (FAMMM) is an autosomal dominant genodermatosis characterized by the presence of a high number of dysplastic nevi and family history of melanoma or pancreatic cancer. Melanomas in FAMMM patients tend to occur at a younger age, although they are clinically similar to sporadic melanomas in terms of overall survival. Case report. A 45 year-old woman with a family history of melanoma, a type II phototype and numerous (>100) nevi was admitted to our Department of Dermatology and Plastic Surgery. Over the past years, the patient underwent several surgical operations to remove pigmented lesions and two are dysplastic nevi. Since 1995, she underwent surgery to remove four melanomas. She is followed for skin examinations including dermoscopy. Conclusion. Identifying high-risk patients for melanoma represents a primary objective for the specialists that are involved in the management of this disease, especially in order to enact all the necessary surveillance and follow-up strategies.

A Rare Cause of Chronic Low Back Pain

Objectives: Autosomal dominant osteopetrosis (ADO) is a rare genetic disease characterized by increased bone mass and density due to defective bone resorption. The aim of this case study is to present the clinical and radiographic features of a 22-year-old male patient with ADO and to serve as a reminder that this rare disease should be considered in the differential diagnosis of chronic low back pain. Materials and methods: A 22-year-old patient with ADO is presented in this case report. Results: Clinical and radiographic features of the patient were consistent with ADO. Conclusions: ADO should be taken into consideration in differential diagnosis of low back pain.

Effect of Aging in the Perception of Health-Related Quality of Life in End-Stage Renal Disease Patients under Online-Hemodiafiltration

This work aimed to evaluate how aging could influence patients' perception of health quality of life (HRQOL), as well as, the effect of aging on dialysis adequacy and in hematological, iron status, inflammatory and nutritional markers. In this transversal study were enrolled 305 ESRD patients under online-hemodiafiltration (OL-HDF) (59.67% males; 64.9 ± 14.3 years old). Data about comorbidities, hematological data, iron status, dialysis adequacy, nutritional and inflammatory markers were collected from patient's records. Moreover, HRQOL score, by using the Kidney Disease Quality of Life-Short Form (KDQOL-SF), was assessed. Analyzing the results according to quartiles of age, significant differences were found for some parameters evaluated by the KDQOL-SF instrument, namely for work status, physical functioning and role-physical, which decreased with increasing age. We also found a higher proportion of diabetic patients, a decrease in creatinine, iron, albumin serum levels, transferrin saturation and nPCR, with increasing age. Moreover, significant negative correlations were found between age and mean cell hemoglobin concentration, iron, transferrin saturation, albumin, nPCR, work status, physical functioning and role-physical. In conclusion, our results showed that aging is associated with a decreased work status, physical functioning and role-physical, with a decreased dialysis adequacy, iron availability and nutritional status, and with an increased proportion of diabetic patients and of patients using central venous catheter, as the vascular access. The knowledge of these changes associated with aging, which have impact in the quality of life of the patients, could be useful in their management.

Homozygosity for the E526V Mutation in Fibrinogen A Alpha-Chain Amyloidosis: The First Report

Systemic hereditary amyloidoses are autosomal dominant diseases associated with mutations in genes encoding ten different proteins. The clinical phenotype has implications on therapeutic approach, but it is commonly variable and largely dependent on the type of mutation. Except for rare cases involving gelsolin or transthyretin, patients are heterozygous for the amyloidogenic variants. Here we describe the first patient identified worldwide as homozygous for a nephropathic amyloidosis, involving the fibrinogen variant associated with the fibrinogen alpha-chain E526V (p.Glu545Val) mutation. In 1989, a 44-year-old woman presented with hypertension, hepatosplenomegaly, nephrotic syndrome, and renal failure. She started hemodialysis in 1990 and 6 years later underwent isolated kidney transplantation from a deceased donor. Graft function and clinical status were unremarkable for 16 years, despite progressively increased left ventricular mass on echocardiography. In 2012, 4 months before death, she deteriorated rapidly with severe heart failure, precipitated by Clostridium difficile colitis and urosepsis. Affected family members developed nephropathy, on average, nearly three decades later, which may be explained by the gene dosage effects on the phenotype of E526V (p.Glu545Val) fibrinogen A alpha-chain amyloidosis.