Heterozygous carriers for Wilson's disease--magnetic spectroscopy changes in the brain.

Wilson's disease (WD) is an autosomal recessive disorder and the WD heterozygote carriers (Hzc) should not exhibit symptoms of the disease. The aim of this study was to assess 12 WD Hzc by brain Proton MR Spectroscopy. In three cases, the levels of caeruloplasmin, and in one case, serum copper, were below our normal range. In two Hzc the aspartate and alanine aminotransferase levels in the blood were slightly increased, however, no ultrasonographic liver changes were detected. The brain metabolite analysis showed a statistically significant higher mean ratio of Glx/Cr and Lip/Cr in MRS in Hzc in both the pallidum and thalami compared to control subjects. Our results suggest that WD Hzc may accumulate free copper in the basal ganglia.

Liver transplantation in a subject with familial hypercholesterolemia carrying the homozygous p.W577R LDL-receptor gene mutation.

Mutations within the low density lipoprotein (LDL)-receptor gene result in familial hypercholesterolemia, an autosomal dominant inherited disease. Clinical homozygous affected subjects die of premature coronary artery disease as early as in early childhood. We identified a girl at the age of five yr with clinical homozygous familial hypercholesterolemia presenting with achilles tendon xanthomas and arcus lipoides. Her total cholesterol reached up to 1050 mg/dL. Molecular characterization of the LDL-receptor gene revealed a homozygous p.W577R mutation. Despite intensive treatment interventions with the combination of diet, statins, colestipol, and LDL-apheresis, the patient developed symptomatic coronary artery disease at the age of 16 yr. Subsequently, orthotopic liver transplantation was performed to cure the defective LDL-receptor gene. Clinical follow-up for almost nine yr post-transplantation revealed excellent liver function, normal liver enzymes, normal LDL-cholesterol, and regression of both tendon xanthomas and symptomatic coronary artery disease. In conclusion, liver transplantation can effectively reduce LDL-cholesterol in a familial hypercholesterolemia recipient with subsequent regression of xanthomas and atherosclerosis. Timing is extremely important in these exceptional cases to exclude the demand for heart transplantation due to severe coronary artery disease. In addition, the identification of the LDL-receptor as etiology of clinical homozygous hypercholesterolemia is a prerequisite once liver transplantation is considered as therapeutic option.

New PPARG mutation leads to lipodystrophy and loss of protein function that is partially restored by a synthetic ligand.

PURPOSE: Familial partial lipodystrophy caused by mutations in the PPARG gene is characterised by altered distribution of subcutaneous fat, muscular hypertrophy and symptoms of metabolic syndrome. PPARG encodes peroxisome proliferator-activated receptor (PPAR)gamma, a nuclear hormone receptor playing a crucial role in lipid and glucose metabolism and in several other cellular regulatory processes. METHODS: PPARG was screened for mutations by direct sequencing in two patients with lipodystrophy, one unaffected family member and 124 controls. Body composition was examined in affected patients, and they were investigated for abnormalities in laboratory results. Functional analysis of the mutant protein was assessed by determining transcriptional activity and possible interference with the wild-type protein. RESULTS: In two patients with familial partial lipodystrophy, we identified a nucleotide substitution in the PPARG gene. This mutation results in the substitution of aspartate by asparagine at residue 424 (D424N) in the ligand-binding domain of PPARgamma. The unaffected family member and all 124 controls did not carry this mutation. D424N PPARgamma had a significantly lower ability than wild-type PPARgamma to activate a PPARgamma-stimulated reporter gene, but did not exert a negative effect on the wild-type protein. Partial activation of D424N PPARgamma was achieved in the presence of the agonist rosiglitazone. CONCLUSION: We report a new PPARG mutation, D424N, which is located in the ligand-binding domain of the protein and leads to familial partial lipodystrophy. D424N PPARgamma exhibited a loss of function, which was partially restored by adding the PPARgamma agonist rosiglitazone, suggesting possible treatment potential of this agent.

Peroxisome proliferator-activated receptor-gamma C190S mutation causes partial lipodystrophy.

CONTEXT: Mutations in PPARG are associated with insulin resistance and familial partial lipodystrophy, a disease characterized by altered distribution of sc fat and symptoms of the metabolic syndrome. The encoded protein, peroxisome proliferator-activated receptor (PPAR)-gamma, plays a pivotal role in regulating lipid and glucose metabolism, the differentiation of adipocytes, and other cellular regulatory processes. OBJECTIVES: The objective of the study was to detect a novel PPARG mutation in a kindred with partial lipodystrophy and analyze the functional characteristics of the mutant protein. PATIENTS AND METHODS: In three subjects with partial lipodystrophy, one unaffected family member, and 124 unaffected subjects, PPARG was screened for mutations by direct sequencing. Body composition, laboratory abnormalities, and hepatic steatosis were assessed in each affected subject. Transcriptional activity was determined, and EMSA was performed to investigate DNA binding capacity of the mutant protein. RESULTS: We identified a PPARG mutation, C190S, causing partial lipodystrophy with metabolic alterations in three affected family members. The mutation was absent in the unaffected family member and unaffected controls. The mutation is located within zinc-finger 2 of the DNA binding domain. C190S PPARgamma has a significantly lower ability to activate a reporter gene than wild-type PPARgamma in absence and presence of rosiglitazone. A dominant-negative effect was not observed. Compared with wild-type PPARgamma, C190S PPARgamma shows a reduced capacity to bind DNA. CONCLUSION: Mutation of a zinc-binding amino acid of PPARgamma leads to an altered protein-DNA binding pattern, resulting in a partial loss of function, which in turn is associated with partial lipodystrophy.

Genes involved in the regulation of intestinal permeability and their role in ulcerative colitis.

OBJECTIVE: Genome-wide association studies have identified single nucleotide polymorphisms in genes that might influence intestinal barrier function (HNF4A, ECM1, CDH1 and LAMB1) to increase the risk for ulcerative colitis (UC). The aim of our study was to detect causative sequence alterations and provide a functional link to a disturbed intestinal permeability (IP) in UC. METHODS: A total of 19 UC patients with increased IP (lactulose/mannitol ratio measured by sugar drink test) were identified from a large database, and exon/intron boundaries, coding and promoter regions of HNF4A, ECM1, CDH1 and LAMB1 were sequenced. Variants with putative protein alterations were studied for an association with IP in 82 UC patients. A case-control analysis including a genotype phenotype correlation was performed in 743 patients with inflammatory bowel disease (IBD) and 473 healthy controls. RESULTS: In UC patients, we identified 11 missense-mutations, 12 synonymous mutations, one putative promoter variant and three variants in introns close to the intron/exon boundaries (CDH1, HNF4A). For several variants prediction tools revealed damaging protein alterations. None of the studied variants, however, showed an association with an increased IP in UC. In the case-control analysis, the frequency of all investigated variants did not differ between UC or Crohn's disease and healthy controls. Furthermore, no significant association was found to a distinct phenotype. CONCLUSIONS: Despite our large sequencing approach, we could not identify protein altering variants in the genes HNF4A, ECM1, CDH1 and LAMB1 which could explain an impaired intestinal barrier function in UC. The functional relevance of these genes in IBD remains unknown.