Inherited disorders of protein glycosylation

Protein N-glycosylation is a widely occurring and vital posttranslational modification in mammalian cells. Although the molecular machinery that is involved in the biosynthesis of these glycoconjugates has been largely identified, the recent discovery of a family of rare inborn diseases in which glycoproteins are abnormally glycosylated has both changed some of our ideas concerning glycoprotein biosynthesis, and given us new insights into this complex process. Advances in the diagnosis of the congenital disorders of glycosylation are well under way and mutations in several of the genes involved in the biosynthesis and maturation of N-linked glycans have been shown to underlie these diseases. By contrast, the chain of events that lead from faulty protein glycosylation to the often severe clinical presentation is an as yet unexplored aspect of these metabolic disorders, and represents a challenge for the future.     

Inherited disorders of transport in the liver

There has been a recent explosion in our understanding of hepatic transport processes. Much of this has resulted from the investigation of human diseases involving the liver and the use of animal models. The physiological roles of many of these transporters have been well characterised previously but have, until now, been resistant to molecular cloning.     

Inherited disorders of ion transport in the intestine

Within the past year, it has been established that the gene mutated in the human disorder congenital chloride diarrhea encodes a major Cl-/HCO3- exchanger at the apical membrane of gut epithelial cells. A major apical Na+/H+ exchanger has also been identified. New insight into metal ion absorption has been gained, and several new transporters without cognate diseases have been cloned.     

Inherited disorders of vitamin B12 utilization

Inborn errors of vitamin B12 (cobalamin) metabolism are associated with homocystinuria and methylmalonic aciduria, either alone or in combination. A number of these disorders have provided the first evidence for the existence of important steps in the transport or metabolism of cobalamin in eukaryotic cells. Eight complementation classes have been defined on the basis of somatic cell hybridization studies. Although the majority of patients present in infancy or early childhood, some are not diagnosed until adolescence or later. For some of these disorders, prenatal diagnosis and therapy with cobalamin during pregnancy has been attempted. Although only males have been described with cblE disease, all of these disorders are presumed to be autosomal recessive in inheritance. The clinical and laboratory aspects of the different complementation classes (cblA-cblG) are reviewed here.     

Inherited disorders of HDL metabolism and atherosclerosis

PURPOSE OF REVIEW: Genetic disorders of HDL metabolism are rare and, as a result, the assessment of atherosclerosis risk in individuals suffering from these disorders has been difficult. Ultrasound imaging of carotid arteries has provided a tool to assess the risk in hereditary hypo and hyperalphalipoproteinemia. This review gives a comprehensive summary. RECENT FINDINGS: Epidemiological studies have unequivocally shown that HDL cholesterol levels are inversely related to coronary artery disease risk, but the literature concerning genetic disorders of HDL metabolism provides less convincing information. Fortuitously, we were able to directly compare carotid intima media thickness data of substantial numbers of individuals with mutations in either apolipoprotein A-I (apoA-I), ATP binding cassette AI (ABCA1), lecithin: cholesterol acyltransferase (LCAT) or cholesteryl ester transfer protein. These data show that carriers of an apoA-I mutation exhibit the most pronounced accelerated atherosclerosis compared with those carrying mutations in ABCA1 and LCAT. Heterozygosity for a non-sense mutation in cholesteryl ester transfer protein did, by contrast, not distinguish carriers from controls in terms of intima media thickness progression. We will discuss these results in the context of the current literature. SUMMARY: Intima media thickness studies have provided evidence that hypoalphalipoproteinemia due to mutations in apoA-I, ABCA1, and LCAT is associated with increased progression of atherosclerosis. In contrast, hyperalphalipoproteinemia as a result of loss of cholesteryl ester transfer protein function is associated with unaltered atherosclerosis progression compared with family controls. This insight is of interest, since it can assist in the prioritizing of antiatherogenic therapy by increasing HDL cholesterol levels.     

Inherited susceptibility of cattle to high-altitude pulmonary hypertension.

This study examines the hypothesis that susceptibility of cattle to high-altitude pulmonary hypertension and heart failure (high mountain disease) is genetically transmitted. Eight offspring of cattle recovered from high mountain disease were considered "susceptible." Eleven offspring of healthy cattle residing at high altitude were considered "resistant." At the resident altitude of 1,524 m, 10-day-old susceptible calves had higher pulmonary arterial pressures than did resistant calves (34 vs.21 mmHg), but at 90 days of age the pressures for the two groups were similar (26 vs. 24 mmHg). After 64 days of exposure to an altitude of 3,048 m, the susceptible calves (87 +/- 7 (SE) vs. 40 +/- 3 mmHg). By 124 days at 3,048 m, all susceptible but none of the resistant calves had developed heart failure. The results indicated that susceptibility to pulmonary hypertension at high altitude was inherited. Susceptible cattle may provide a useful model of human hypoxic pulmonary hypertension.     

Inherited hemoglobin disorders in an Afro-Amazonian community: Saracura

The most common hemoglobinopathies, viz, hemoglobins S and C, and α- and β-thalassemias, were investigated through the molecular screening of 116 subjects from the community of Saracura, comprising fugitive African slaves from farms of the municipality of Santarém, in the west of Pará State, Brazilian Amazon. The observed frequency of the HBB*S gene (0.9%) was significantly lower than that encountered in other Afro-derived communities in the region. Concomitantly, the absence of the HBB*C allele has been reported for most of the Afro-Amazonian communities thus far studied. As remnant populations of quilombos are generally small, the heterogeneous distribution of HBB*S and HBB*C alleles among them is probably due to genetic drift and/or founder effect. The observed frequency of 3.7 kb deletion in Saracura (8.5%) was consistent with the African origin of the population, with a certain degree of local differentiation and admixture with individuals of Caucasian ancestry, placed in evidence by the occurrence of - -(MED) deletion (1.2%), a common mutation in Mediterranean regions. As regards β-thalassemia, among the seven different mutations found in Saracura, three β^o and two β⁺ mutations were of Mediterranean origin, and two β⁺ of African. Thus, only 28% of the local β-thalassemia mutations found in Saracura were of African origin.     

Inherited disorders of iron storage and transport.

Diverse hereditary disorders associated with iron accumulation cause widespread organ damage. New insights into cellular pathways of iron transport have emerged from the identification of molecules implicated in heritable defects of iron metabolism. Unravelling the genetic basis of rare variants of haemochromatosis should provide vital functional information to further our mechanistic understanding of iron homeostasis.     

Genome-wide association and biological pathway analysis for milk-fat composition in Danish Holstein and Danish Jersey cattle

Background

The milk fat profile of the Danish Holstein (DH) and Danish Jersey (DJ) show clear differences. Identification of the genomic regions, genes and biological pathways underlying the milk fat biosynthesis will improve the understanding of the biology underlying bovine milk fat production and may provide new possibilities to change the milk fat composition by selective breeding. In this study a genome wide association scan (GWAS) in the DH and DJ was performed for a detailed milk fatty acid (FA) profile using the HD bovine SNP array and subsequently a biological pathway analysis based on the SNP data was performed.

Results

The GWAS identified in total 1,233 SNPs (FDR < 0.10) spread over 18 chromosomes for nine different FA traits for the DH breed and 1,122 SNPs (FDR < 0.10) spread over 26 chromosomes for 13 different FA traits were detected for the DJ breed. Of these significant SNPs, 108 SNP markers were significant in both DH and DJ (C14-index, BTA26; C16, BTA14; fat percentage (FP), BTA14). This was supported by an enrichment test. The QTL on BTA14 and BTA26 represented the known candidate genes DGAT and SCD. In addition we suggest ACSS3 to be a good candidate gene for the QTL on BTA5 for C10:0 and C15:0. In addition, genetic correlations between the FA traits within breed showed large similarity across breeds. Furthermore, the biological pathway analysis revealed that fat digestion and absorption (KEGG04975) plays a role for the traits FP, C14:1, C16 index and C16:1.

Conclusion

There was a clear similarity between the underlying genetics of FA in the milk between DH and DJ. This was supported by the fact that there was substantial overlap between SNPs for FP, C14 index, C14:1, C16 index and C16:1. In addition genetic correlations between FA showed a similar pattern across DH and DJ. Furthermore the biological pathway analysis suggested that fat digestion and absorption KEGG04975 is important for the traits FP, C14:1, C16 index and C16:1.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-1112) contains supplementary material, which is available to authorized users.     

Respiratory disorders in Manitoba cattle farmers.

A group of 76 cattle farmers from southern Manitoba answered the National Heart, Lung, and Blood Institute questionnaire on respiratory symptoms and supplementary questions on farming and farming-related syndromes. Lung function was tested, serum was examined for precipitating antibodies, and skin testing with common allergens was performed. Analysis of the men''s answers revealed a high prevalence of chronic respiratory symptoms among the farmers in all categories of smoking history, and the presence of these symptoms was significantly associated with a history of symptoms related to handling mouldy hay or grain; 51% of the men had chronic symptoms and 55% had symptoms related to crop handling. In seven farmers (9%) the symptoms related to crop handling suggested an attack of farmer''s lung. One other farmer, with a history of illness after handling mouldy hay, had a reduced total lung capacity, and in 18 the ratio of the forced expiratory volume in the first second to the forced vital capacity was lower than predicted. Precipitating antibodies against Thermoactinomyces were absent in all farmers, but two farmers had antibodies against Aspergillus ruber. Immediate hypersensitivity was found in 16 (21%) of the farmers; sensitivity to Dermatophagoides farinae was commonest.     

Genetic disorders in beef cattle: a review

The main purpose of present review is to describe and organize autosomal recessive disorders (arachnomelia, syndactylism, osteopetrosis, dwarfism, crooked tail syndrome, muscular hyperplasia, glycogen storage disease, protoporphyria), which occur among beef cattle, and methods that can be applied to detect these defects. Prevalence of adverse alleles in beef breeds happens due to human activity—selections of favorable features, e.g. developed muscle tissue. Unfortunately, carriers of autosomal recessive diseases are often characterized by these attributes. Fast and effective identification of individuals, that may carry faulty genes, can prevent economical losses.     

Studies on the C blood group system in three Danish cattle breeds1

The preparation of anti-X' and the non-linear relation of X, and X' are described. The C system phenogroups as determined by means of 12 internationally recognized antisera in populations of three Danish cattle breeds are given together with gene frequency estimates.     

A hereditary disposition for bovine peripheral nerve sheath tumors in Danish Holstein cattle

Background

Peripheral nerve sheath tumors (PNSTs) are frequently found in Danish cattle at slaughter. Bovine PNSTs share several gross and histopathological characteristics with the PNSTs in humans with heritable neurofibromatosis syndromes. The aim of the present study was to investigate a possible hereditary disposition to PNSTs in dairy cattle by statistical analysis performed on data from 567 cattle with PNSTs. Furthermore, a preliminary genome-wide association study (GWAS) was performed on DNA isolated from 28 affected and 28 non-affected Holstein cows to identify loci in the bovine genome involved in the development of PNSTs.

Results

PNSTs were significantly more common in the Danish Holstein breed than in other breeds with 0.49% of Danish Holsteins slaughtered during an eight-year-period having PNSTs. PNSTs also occurred significantly more frequently in the offspring of some specific Holstein sires. Examination of three generation pedigrees showed that these sires were genetically related through a widely used US Holstein sire. The PNSTs included in GWAS were histologically classified as neurofibroma-schwannoma (43%), schwannoma (36%) and neurofibroma (21%) and derived from Holstein cows with multiple PNSTs. A single SNP on chromosome 27 reached genome-wide significance.

Conclusions

Gross and histological characteristics of bovine PNSTs are comparable to PNSTs in humans (schwannomatosis). Danish Holsteins are genetically disposed to develop PNSTs but the examined materials are insufficient to allow determination of the mode of inheritance.

     

Inherited disorders of the skin in human and mouse: from development to differentiation

The last ten years has revealed some of the key players in the development and differentiation of the hair follicle and the epidermis in general. In this review, we discuss how our current understanding of these processes has been made possible by the elucidation of the molecular basis of human inherited diseases and mouse mutants which display defects in the hair and epidermis. For examples, the study of ectodermal dysplasias and the basal cell carcinoma predisposition disease Gorlin syndrome have allowed the determination of signalling hierarchies critical in the formation of the hair follicle. Epidermolytic diseases and hyperkeratoses have focussed attention on the importance of the programs of keratin expression, while ichthyoses provide insight in the final stage of epidermal development, cornification. Finally, the increasing range of diseases and mouse models exhibiting alopecias are revealing the critical pathways in control of the hair follicle cycle.     

Reproductive disorders in dairy cattle. II. Interrelationships between pre-or post-service infectious and functional disorders

This retrospective study was aimed at investigating the interrelationships between the various post-partum reproductive disorders whose incidence distribution was reported in a previous paper. There were 343 calving cows, and 319 of them were inseminated at least once. Although approximately one-third of the cows suffered from metritis, its influence on subsequent pathology was only minor. No within-animal relationship could be found between post-partum cyclic anestrus and post-AI anestrus. The distribution of repeat breeding cows showed that almost half of them also had post-AI anestrus, and only 17% had no other disorders. Previous metritis accounted for only 10% of these cases. Embryonic mortality was related only to post-partum cyclic anestrus. Finally, it was found that approximately half of the cows suffered from more than one reproductive disorder with many different relations between the disorders within individuals during post partum. In conclusion, optimal efficiency of post-partum reproduction requires careful checking of all possible disorders.