Uveitis Associated with Monogenic Autoinflammatory Syndromes in Children.

Monogenic autoinflammatory syndromes (MAISs), are caused by pathogenic genetic variants in the innate immune system, leading to dysregulation and aberrant inflammasome activation spontaneously or with minimal triggering. The diagnosis and treatment of MAISs can be intricate, relying on an increased recognition of potential differential diagnoses. This review examines the clinical features of MAIS, with a special focus on uveitis. It also evaluates treatment options and assesses the effects of activating molecular and cytokine pathways.

Linkage validation of RP25 Using the 10K genechip array and further refinement of the locus by new linked families.

Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of retinal dystrophies, characterised by rod photoreceptor cell degeneration with autosomal recessive RP (arRP) as the commonest form worldwide. To date, a total of 26 loci have been reported for arRP, each having a prevalence of 1-5%, except for the RP25 locus which was identified as the genetic cause of 14% of arRP cases in Spain. In order to validate the original linkage of RP25, we undertook a total genome scan using the 10K GeneChip mapping array on three of the previously linked families. The data obtained supported the initial findings of linkage. Additionally, linkage analysis in 18 newly ascertained arRP families was performed using microsatellite markers spanning the chromosome 6p12.1-q15 interval. Five out of the 18 families showed suggestive evidence of linkage to RP25, hence supporting the high prevalence of this locus in the Spanish population. Furthermore, the finding of a crossover in one of these families is likely to have refined the disease interval from the original 16 cM to only a 2.67 cM region between D6S257 and D6S1557.

Large-scale molecular analysis of a 34 Mb interval on chromosome 6q: major refinement of the RP25 interval.

A large scale bioinformatics and molecular analysis of a 34 Mb interval on chromosome 6q12 was undertaken as part of our ongoing study to identify the gene responsible for an autosomal recessive retinitis pigmentosa (arRP) locus, RP25. Extensive bioinformatics analysis indicated in excess of 110 genes within the region and we also noted unfinished sequence on chromosome 6q in the Human Genome Database, between 58 and 61.2 Mb. Forty three genes within the RP25 interval were considered as good candidates for mutation screening. Direct sequence analysis of the selected genes in 7 Spanish families with arRP revealed a total of 244 sequence variants, of which 67 were novel but none were pathogenic. This, together with previous reports, excludes 60 genes within the interval ( approximately 55%) as disease causing for RP. To investigate if copy number variation (CNV) exists within RP25, a comparative genomic hybridization (CGH) analysis was performed on a consanguineous family. A clone from the tiling path array, chr6tp-19C7, spanning approximately 100-Kb was found to be deleted in all affected members of the family, leading to a major refinement of the interval. This will eventually have a significant impact on cloning of the RP25 gene.

Genetic analysis of FAM46A in Spanish families with autosomal recessive retinitis pigmentosa: characterisation of novel VNTRs.

Retinitis pigmentosa (RP) is a group of retinal dystrophies characterised primarily by rod photoreceptor cell degeneration. Exhibiting great clinical and genetic heterogeneity, RP be inherited as an autosomal dominant (ad) and recessive (ar), X-linked (xl) and digenic disorder. RP25, a locus for arRP, was mapped to chromosome 6p12.1-q14.1 where several retinal dystrophy loci are located. A gene expressed in the retina, FAM46A, mapped within the RP25 locus, and computational data revealed its involvement in retinal signalling pathways. Therefore, we chose to perform molecular evaluation of this gene as a good candidate in arRP families linked to the RP25 interval. A comprehensive bioinformatic and retinal tissue expression characterisation of FAM46A was performed, together with mutation screening of seven RP25 families. Herein we present 4 novel sequence variants, of which one is a novel deletion within a low complexity region close to the initiation codon of FAM46A. Furthermore, we have characterised for the first time a coding tandem variation in the Caucasian population. This study reports on bioinformatic and moleculardata for the FAM46A gene that may give a wider insight into the putative function of this gene and its pathologic relevance to RP25 and other retinal diseases mapping within the 6q chromosomal interval.

A novel genetic study of Chinese families with autosomal recessive retinitis pigmentosa.

Autosomal recessive retinitis pigmentosa (arRP) is the commonest form of RP worldwide. To date 22 loci have been implicated in the pathogenesis of this disease; however none of these loci independently account for a significant proportion of recessive RP. Linkage studies of arRP in consanguineous families have been mainly based on homozygosity mapping, but this strategy cannot be applied in the case of non-consanguineous families. Therefore, we implemented a systematic approach for identifying the disease locus in three non-consanguineous Chinese families with arRP. Initially, linkage analysis using SNPs/microsatellite markers or mutation screening of known arRP genes excluded all loci/genes except RP25 on chromosome 6. Subsequently a whole genome scan for the three families using the 10K GeneChip Mapping Array was performed, in order to identify the possible disease locus. To the best of our knowledge this is the first report on the utilisation of the 10K GeneChip to study linkage in non-consanguineous Chinese arRP. This analysis indicates that the studied families are probably linked to the RP25 locus, a well defined arRP locus in other populations. The identification of another ethnic group linked to RP25 is highly suggestive that this represents a major locus for arRP.

BIGH3 mutation in a Bangladeshi family with a variable phenotype of LCDI.

AIMS: To report a Bangladeshi family displaying intrafamilial phenotypic heterogeneity of lattice corneal dystrophy type I (LCDI) and to identify the causative mutation. METHODS: Molecular genetic analysis was performed on DNA extracted from all members of the family. Exons of BIGH3 gene were amplified by polymerase chain reaction. Gene mutation and polymorphisms were identified by heteroduplex and sequence analyses. Segregation of the mutation in the family was confirmed by restriction digestion of amplified gene fragments. RESULTS: A heterozygous C --> T transition at the first nucleotide position of codon 124 of the BIGH3 gene was detected in the three affected members and not in the unaffected members of the family. CONCLUSIONS: This is the first report of BIGH3 gene mutation in a Bangladeshi family with phenotypic heterogeneity. This study confirms that BIGH3 gene screening should be undertaken for proper classification of corneal dystrophy, especially in the absence of histopathological examination.

A clinical, histopathological, and genetic study of Avellino corneal dystrophy in British families.

AIMS: To establish a clinical, histopathological, and genetic diagnosis in two unrelated British families with Avellino corneal dystrophy (ACD). METHODS: Genomic DNA was extracted from peripheral blood leucocytes of all members participating in the study. Exons 4 and 12 of the human transforming growth factor beta induced (BIGH3) gene were amplified by polymerase chain reaction. The mutation and polymorphism were identified by direct sequencing and restriction digest analysis. A review of the patients' clinical symptoms and signs was undertaken and a histopathological study on corneal specimen obtained from the proband of one family after keratoplasty was performed. RESULTS: A heterozygous G to A transition at the second nucleotide position of codon 124 of BIGH3 gene was detected in all affected members of both families. This mutation changes an arginine residue to a histidine. The clinical diagnosis for ACD was more evident with advancing age. Histopathological study revealed granular deposits in the anterior stroma and occasional positive Congo red areas of amyloid deposition in the mid to deep stroma typical of ACD. CONCLUSIONS: This is the first report of ACD families in the United Kingdom and, furthermore, of BIGH3 gene mutation in British patients with this rare type of corneal dystrophy. The results indicate that BIGH3 gene screening along with clinical and histopathological examinations is essential for the diagnosis and clinical management of corneal dystrophies.

A novel keratocan mutation causing autosomal recessive cornea plana.

PURPOSE: Mutations in keratocan (KERA), a small leucine-rich proteoglycan, have recently been shown to be responsible for cases of autosomal recessive cornea plana (CNA2). A consanguineous pedigree in which cornea plana cosegregated with microphthalmia was investigated by linkage analysis and direct sequencing. METHODS: Linkage was sought to polymorphic microsatellite markers distributed around the CNA2 and microphthalmia loci (arCMIC, adCMIC, NNO1, and CHX10) using PCR and nondenaturing polyacrylamide gel electrophoresis before KERA was directly sequenced for mutations. RESULTS: Positive lod scores were obtained with markers encompassing the CNA2 locus, the maximum two-point lod scores of 2.18 at recombination fraction theta = 0 was obtained with markers D12S95 and D12S327. Mutation screening of KERA revealed a novel single-nucleotide substitution at codon 215, which results in the substitution of lysine for threonine at the start of a highly conserved leucine-rich repeat motif. Structural modeling predicts that the motifs are stacked into an arched beta-sheet array and that the effect of the mutation is to alter the length and position of one of these motifs. CONCLUSIONS: This report describes a novel mutation in KERA that alters a highly conserved motif and is predicted to affect the tertiary structure of the molecule. Normal corneal function is dependent on the regular spacing of collagen fibrils, and the predicted alteration of the tertiary structure of KERA is the probable mechanism of the cornea plana phenotype.

Plant proteins in milk replacers for rearing buffalo calves. I. Effect of replacing half of the milk proteins by plant proteins on the preweaning performance of buffalo calves.

In an experiment, 12 female and 8 male buffalo calves aged 3 to 4 weeks with an average of 65.2 kg live body weight were divided into 4 equal groups. Group 1 received dried skim milk plus non-milk fat. In groups 2, 3, and 4, 50% of the milk protein were replaced by American soybean flour, Egyptian soya meal, or corn glutine. Scouring occurred in all groups during the first three weeks. Death losses occurred in group 2 (2 calves) and 4 (1 calf). During the first three experimental weeks the calves consumed on average 828, 868, 847, 696 g dry matter (DM) as liquids. The average daily gain (ADG) was 229, 215, 252, 48 g/d, respectively. The energy consumption reached 4.1, 4.6, 3.8, 16.6 TDN/kg ADG. During the second period, the calves consumed 1.57, 1.45, 1.55, 1.65 kg DM as liquid and solid feedstuff. Up to a live body weight of 90 kg they had a daily increase of 695, 611, 593, 600 g. The energy used amounted to 1.98, 2.08, 2.28, 2.40 TDN/kg ADG. The apparent digestibility of the crude protein was 95, 92, 91, 92% during the first period and 81, 77, 76, 73% during the second period.

Plant protein in milk replacers for rearing buffalo calves. II. Effect of replacing 75% of the milk proteins by plant proteins on the preweaning performance of buffalo calves.

In an experiment, 9 female and 6 male buffalo calves at the age of 3 to 4 weeks were divided into 3 groups. The animals were given milk replacers in which 75% of the dried skim milk protein had been replaced by American soybean flour (ASP), Egyptian soya meal (ESP), or corn glutine (GP). Scouring occurred in all groups during the first 3 weeks of the experiment, continuing up to the fourth week in groups ESP and GP. In groups ESP and GP one calf each died. During the first 3 weeks of the experiment, the calves consumed on average 747, 631, 787 g dry matter (DM) as liquids. They achieved live weight gains of 314, 83, -286 g/d, with significant differences between the groups. The digestibility of the crude protein was 73, 74, 70%. During the second period--up to 70 or 62.5 kg live body weight--only groups ASP and ESP were investigated. The calves consumed 1.64 or 1.66 kg DM/d as liquid and dry feedstuff. The average daily weight gain was 3.87 or 3.50 TDN/kg ADG. During this period, the crude protein was digested by 76 or 73%.

Specific gravity measurements of lamb carcass joints.

10 Ossimi lamb carcasses were used to determine the specific gravity values of different joint cuts. The correlation coefficients were established between the specific gravities of these joints and the percentages of fat and muscle in the rib saddle joint. It was found that the gravity of different carcass sections was significantly related to the muscle and fat percentages in the rib saddle joint. The results indicate that the specific gravity values of carcass sections can be utilized for a practical estimate and assessment of carcass components.

In vivo platelet activity and lipoprotein patterns in coronary artery disease.

In order to determine the effect of hyperlipoproteinemia on the in vivo formation of circulating platelet aggregates (CPA) in patients with coronary artery disease, CPA ratios, lipoprotein pattern, serum cholesterol and triglycerides were determinated in 80 male patients with stable coronary artery disease and hyperlipoproteinemia. Similar studies were performed in 30 male age-matched patients with stable coronary artery disease without hyperlipoproteinemia and 60 male age-matched healthy volunteers; the latter group served as controls. CPA ratios were significantly lowered; i.e. an increase was observed in circulating platelet aggregates in 24 patients without hyperlipoproteinemia as compared with the values in the control group. All the cardiac patients with hyperlipoproteinemia had a significantly lower CPA ratio than the patients without hyperlipoproteinemia. Moreover, the lowering in CPA ratio was more marked among patients with type II a hyperlipoproteinemia than in those with type IV. We think that this in vivo test for platelet function may throw more light on the effect of hyperlipoproteinemia on the in vivo aggregation of circulating platelets in patients with coronary artery disease.