Oculocutaneous albinism (OCA) is a group of inherited disorders of melanin biosynthesis characterized by a generalized reduction in pigmentation of hair, skin and eyes. The prevalence of all forms of albinism varies considerably worldwide and has been estimated at approximately 1/ 17,000, suggesting that about 1 in 70 people carry a gene for OCA. The clinical spectrum of OCA ranges, with OCA1A being the most severe type with a complete lack of melanin production throughout life, while the milder forms OCA1B, OCA2, OCA3 and OCA4 show some pigment accumulation over time. Clinical manifestations include various degrees of congenital nystagmus, iris hypopigmentation and translucency, reduced pigmentation of the retinal pigment epithelium, foveal hypoplasia, reduced visual acuity usually (20/60 to 20/400) and refractive errors, color vision impairment and prominent photophobia. Misrouting of the optic nerves is a characteristic finding, resulting in strabismus and reduced stereoscopic vision. The degree of skin and hair hypopigmentation varies with the type of OCA. The incidence of skin cancer may be increased. All four types of OCA are inherited as autosomal recessive disorders. At least four genes are responsible for the different types of the disease (TYR, OCA2, TYRP1 and MATP). Diagnosis is based on clinical findings of hypopigmentation of the skin and hair, in addition to the characteristic ocular symptoms. Due to the clinical overlap between the OCA forms, molecular diagnosis is necessary to establish the gene defect and OCA subtype. Molecular genetic testing of TYR and OCA2 is available on a clinical basis, while, at present, analysis of TYRP1 and MATP is on research basis only. Differential diagnosis includes ocular albinism, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Griscelli syndrome, and Waardenburg syndrome type II. Carrier detection and prenatal diagnosis are possible when the disease causing mutations have been identified in the family. Glasses (possibly bifocals) and dark glasses or photocromic lenses may offer sufficient help for reduced visual activity and photophobia. Correction of strabismus and nystagmus is necessary and sunscreens are recommended. Regular skin checks for early detection of skin cancer should be offered. Persons with OCA have normal lifespan, development, intelligence and fertility. Disease name Oculocutaneous albinism DefinitionOculocutaneous albinism (OCA) is a group of four autosomal recessive disorders caused by either a complete lack or a reduction of melanin biosynthesis in the melanocytes

Peroxisome proliferator-activated receptor-g coactivator-1 (PGC-1) is a novel transcriptional co-activator of a series of nuclear receptors including peroxisome proliferator-activated receptor-g (PPAR-g), a transcription factor involved in adipogenesis and a functional receptor for thiazolidinediones [1,2]. Similarly, PGC-1 is a coactivator of peroxisome proliferator-activated receptor-a (PPAR-a), which plays a key role in the transcriptional control of genes encoding mitochondrial fatty acid beta-oxidation enzymes [3]. Studies in cultured muscle-cell lines show that PGC-1 stimulates mitochondrial biogenesis and respiration through an induction of uncoupling protein 2 and through regulation of the nuclear respiratory factors [2]. Thus, PGC-1 is a key factor in the stimulation of adaptive thermogenesis, e. g. during high caloric diets or cold exposure. It has recently Diabetologia (2001)

No abstract

Type II (non-insulin-dependent) diabetes mellitus is phenotypically and genetically a heterogeneous disorder resulting from defects in insulin secretion and insulin action [1]. Mutations in several genes linked to monogenic forms of Type II diabetes have been identified [2±7] and recently, a common G®A transition within intron 3 of the CAPN10 gene (UCSNP-43) in combination with specific polymorphisms in other locations within CAPN10 was associated with Type II diabetes [8]. However, in the vast majority of Type II diabetic patients the genetic mechanism and the pathogenesis behind the disease are still not clear.The peroxisome proliferator-activated receptor-g (PPAR-g) is a transcription factor, involved in adipogenesis and in the regulation of adipocyte gene expression [9]. PPARg exists in three different isoforms [10]. Two mutations in the ligand-binding domain of PPAR-g, Pro467Leu and Val290Met, were found in Diabetologia (2001) Abstract Aims/hypothesis. We examined whether the Pro12-Ala polymorphism of the human peroxisome proliferator-activated receptor-g2 (PPAR-g2) gene was related to altered insulin sensitivity among glucose-tolerant subjects or a lower accumulated incidence or prevalence of IGT and Type II (non-insulin-dependent) diabetes mellitus among Scandinavian Caucasians.Methods. The Pro12Ala polymorphism was examined using PCR-RFLP. Whole-body insulin sensitivity measured under hyperinsulinaemic-euglycaemic conditions was estimated in a population-based sample of 616 glucose tolerant Swedish Caucasian men at age 70. In addition, insulin sensitivity index was measured using IVGTT and Bergman minimal modelling in a population-based sample of 364 young healthy Danish Caucasians. Finally, we evaluated whether the polymorphism predicted Type II diabetes and IGT in 841 seventy-year-old Swedish men. A case-control study was carried out in 654 unrelated Danish Type II diabetic patients and 742 Danish glucose tolerant subjects matched for age and sex.

The conserved oligomeric Golgi (COG) complex is involved in intracellular vesicular transport, and is composed of eight subunits distributed in two lobes, lobe A (COG1-4) and lobe B (COG5-8). We describe fourteen individuals with Saul-Wilson syndrome, a rare form of primordial dwarfism with characteristic facial and radiographic features. All affected subjects harbored heterozygous de novo variants in COG4, giving rise to the same recurrent amino acid substitution (p.Gly516Arg). Affected individuals' fibroblasts, whose COG4 mRNA and protein were not decreased, exhibited delayed anterograde vesicular trafficking from the ER to the Golgi and accelerated retrograde vesicular recycling from the Golgi to the ER. This altered steady-state equilibrium led to a decrease in Golgi volume, as well as morphologic abnormalities with collapse of the Golgi stacks. Despite these abnormalities of the Golgi apparatus, protein glycosylation in sera and fibroblasts from affected subjects was not notably altered, but decorin, a proteoglycan secreted into the extracellular matrix, showed altered Golgi-dependent glycosylation. In summary, we define a specific heterozygous COG4 substitution as the molecular basis of Saul-Wilson syndrome, a rare skeletal dysplasia distinct from biallelic COG4-CDG.

Aims/hypothesis. The aim of this study was to examine the prevalence and nature of mutations in HNF4α/ MODY1, GCK/MODY2 and HNF-1α/MODY3 genes in Czech subjects with clinical diagnosis of MODY. Methods. We studied 61 unrelated index probands of Czech origin (28 males, 33 females) with a clinical diagnosis of MODY and 202 family members. The mean age of probands was 22.7±12.0 years (range, 6-62) and the mean age at the first recognition of hyperglycaemia was 14.7±6.0 years (range, 1-25). The promotor and coding regions inclusive intron exon boundaries of the HNF-4α, GCK and HNF-1α genes were examined by PCR-dHPLC (HNF-1α and GCK) and direct sequencing. Results. We identified 20 different mutations in the HNF-4α, GCK and HNF-1α in 29 families (48% of all families studied), giving a relative prevalence of 5% of MODY1, 31% of MODY2 and 11.5% of MODY3 among the Czech kindred with MODY. Three of 3, 10 of 11 and 1 of 6 of the mutations identified in HNF-4α, GCK and HNF-1α respectively, were new. Conclusion/interpretation. Of the families 48% carried mutations in the MODY1-3 genes and of the identified mutations 70% were new. In 52% of Czech families with clinical characteristics of MODY, no mutations were found in the analysed genes. This finding shows that the majority of MODY mutations in a central European population are local and that other MODY genes could be responsible for autosomal dominant transmission of diabetes mellitus. [Diabetologia (2003) 46:291-295] Keywords MODY, genetics, mutation, glucokinase, HNF-1α, HNF-4α, MODY X. Corresponding author: J. Lebl, Department of Paediatrics, 3rd Faculty of Medicine, Charles University, Vinohradska 159, 100 81 Prague 10, Czech Republic E-mail: lebl@fnkv.cz Abbreviations: GCK, Glucokinase; HNF-1α, hepatocyte nuclear factor-1alpha; HNF-4α, hepatocyte nuclear factor-4alpha; IPF-1 insulin promoter factor-1; HNF-1β, hepatocyte nuclear factor-1beta; dHPLC, denatured high performance liquid chromatography; RFLP, restriction fragment length polymorphism; OHA, oral hypoglycaemic agents. Six known MODY subtypes are caused by mutations in genes encoding the hepatocyte nuclear factor-4α (HNF-4α), glucokinase (GCK), hepatocyte nuclear factor-1α (HNF-1α), insulin promoter factor-1 (IPF-1), hepatocyte nuclear factor-1β (HNF-1β) and NeuroD1 respectively [1].The relative prevalence of distinct MODY subtypes differs substantially in studies in various populations [2,3,4], mutations in GCK representing from 8 to 63% and HNF-1α mutations for 13 to 64% of all subjects with MODY [5]. Mutations in the HNF-4α, IPF-1, HNF-1β and NeuroD1 have been recognised in single families only, while additional unknown MODY genes ("MODY X") may cause between 16 and 45% of cases of MODY [3].We initiated a study of genetic epidemiology of MODY in the Czech republic, as no data on the relaMaturity Onset Diabetes of the Young is a genetically heterogeneous form of diabetes mellitus, characterised by an autosomal dominant inheritance, by early age at onset and by a primary defect in beta-cell function.

Aims/hypothesis Plasma cell membrane glycoprotein 1 (PC-1) inhibits insulin signalling by direct interaction with the insulin receptor α subunit. This inhibition is enhanced by the minor Q allele of the K121Q polymorphism (rs1044498) in the gene (ENPP1) encoding PC-1. This polymorphism has been studied in relation to insulin resistance, type 2 diabetes and obesity in several populations with conflicting results. We assessed the impact of the ENPP1 K121Q polymorphism on type 2 diabetes, obesity and quantitative metabolic traits in 7,333 Danes. Subjects and methods The K121Q polymorphism was genotyped in the population-based Inter99 study cohort (5,961 subjects) and in a group of 1,386 patients with type 2 diabetes. All subjects were Danish whites.Results No significant associations with type 2 diabetes or related quantitative metabolic traits, including measures of insulin resistance, were detected. However, a meta-analysis of the present and published studies revealed an association with type 2 diabetes (odds ratio per Q allele, 1.17 [95% CI 1.10-1.25], p=1×10 −6 ). In case-control studies comparing subjects of different BMI strata, we observed a putative association of the codon 121 QQ genotype with being overweight (BMI>25 kg/m 2 ; odds ratio 1.63 [95% CI 1.09-2.46], p=0.015), an association not observed when comparing other levels of BMI or when analysing BMI as a quantitative trait. Conclusions/interpretation In a meta-analysis, the ENPP1 codon 121 Q allele associates with type 2 diabetes. However, a similar association was not found in the present study of Danish white subjects. The effect of this variant on obesity in Danish subjects is contentious and further study is needed.

TYR is the major OCA gene in Denmark, but several patients do not have mutations in the investigated genes. A relatively large fraction of patients were observed with AROA, and of those 52% had no mutations compared with 15% of those with OCA.