Uterine leiomyomata with deletions of Ip represent a distinct cytogenetic subgroup associated with unusual histologic features

De zelf-assemblage van kleine moleculaire bouwstenen tot grotere supramoleculaire systemen is een belangrijke benadering om nieuwe materialen met nanodimensies te maken. Een bekend voorbeeld zijn de organogelatoren. Dit zijn moleculen die aggregeren in oplossing, bijvoorbeeld via waterstofbruggen, en zo een netwerk vormen dat in staat is om de oplosmiddelmoleculen vast te houden, waardoor er een gel is gevormd. Zie: Samenvatting

Identification and characterization of a mutation, in the human UDP-galactose-4-epimerase gene, associated with generalized epimerase-deficiency galactosemia.

Epimerase-deficiency galactosemia results from impairment of the human enzyme UDP-galactose-4-epimerase (hGALE). We and others have identified substitution mutations in the hGALE alleles of patients with the clinically mild, peripheral form of epimerase deficiency. We report here the first identification of an hGALE mutation in a patient with the clinically severe, generalized form of epimerase deficiency. The mutation, V94M, was found on both GALE alleles of this patient. This same mutation also was found in the homozygous state in two additional patients with generalized epimerase deficiency. The specific activity of the V94M-hGALE protein expressed in yeast was severely reduced with regard to UDP-galactose and partially reduced with regard to UDP-N-acetylgalactosamine. In contrast, two GALE-variant proteins associated with peripheral epimerase deficiency, L313M-hGALE and D103G-hGALE, demonstrated near-normal levels of activity with regard to both substrates, but a third allele, G90E-hGALE, demonstrated little, if any, detectable activity, despite near-normal abundance. G90E originally was identified in a heterozygous patient whose other allele remains uncharacterized. Thermal lability and protease-sensitivity studies demonstrated compromised stability in all of the partially active mutant enzymes

Structural and molecular biology of type I galactosemia: Disease-associated mutations

Type I galactosemia results from reduced galactose 1-phosphate uridylyltransferase (GALT) activity. Signs of disease include damage to the eyes, brain, liver, and ovaries. However, the exact nature and severity of the pathology depends on the mutation(s) in the patient's genes and his/her environment. Considerable enzymological and structural knowledge has been accumulated and this provides a basis to explain, at a biochemical level, impairment in the enzyme in the more than 230 disease-associated variants, which have been described. The most common variant, Q188R, occurs close to the active site and the dimer interface. The substitution probably disrupts both UDP-sugar binding and homodimer stability. Other alterations, for example K285N, occur close to the surface of the enzyme and most likely affect the folding and stability of the enzyme. There are a number of unanswered questions in the field, which require resolution. These include the possibility that the main enzymes of galactose metabolism form a supramolecular complex and the need for a high resolution crystal structure of human GALT. (C) 2011 IUBMB IUBMB Life, 63(11): 949-954, 201

Expression profiling of uterine leiomyomata cytogenetic subgroups reveals distinct signatures in matched myometrium: transcriptional profilingof the t(12;14) and evidence in support of predisposing genetic heterogeneity.

Uterine leiomyomata (UL), the most common neoplasm in reproductive-age women, are classified into distinct genetic subgroups based on recurrent chromosome abnormalities. To develop a molecular signature of UL with t(12;14)(q14-q15;q23-q24), we took advantage of the multiple UL arising as independent clonal lesions within a single uterus. We compared genome-wide expression levels of t(12;14) UL to non-t(12;14) UL from each of nine women in a paired analysis, with each sample weighted for the percentage of t(12;14) cells to adjust for mosaicism with normal cells. This resulted in a transcriptional profile that confirmed HMGA2, known to be overexpressed in t(12;14) UL, as the most significantly altered gene. Pathway analysis of the differentially expressed genes showed significant association with cell proliferation, particularly G1/S checkpoint regulation. This is consistent with the known larger size of t(12;14) UL relative to karyotypically normal UL or to UL in the deletion 7q22 subgroup. Unsupervised hierarchical clustering demonstrated that patient variability is relatively dominant to the distinction of t(12;14) UL compared with non-t(12;14) UL or of t(12;14) UL compared with del(7q) UL. The paired design we employed is therefore important to produce an accurate t(12;14) UL-specific gene list by removing the confounding effects of genotype and environment. Interestingly, myometrium not only clustered away from the tumors, but generally separated based on associated t(12;14) versus del(7q) status. Nine genes were identified whose expression can distinguish the myometrium origin. This suggests an underlying constitutional genetic predisposition to these somatic changes which could potentially lead to improved personalized management and treatment