[Molecular genetics of hemochromatosis].
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Animals↗
Biomedical subjects
B Hermelin
Publications and source records attributed to B Hermelin.
MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis.
BACKGROUND & AIMS: Many studies indicate that gallstone susceptibility has genetic components. MDR3 is the phosphatidylcholine translocator across the hepatocyte canalicular membrane. Because phospholipids are a carrier and a solvent of cholesterol in hepatic bile, we hypothesized that a defect in the MDR3 gene could be the genetic basis for peculiar forms of cholesterol gallstone disease, in particular those associated with symptoms and cholestasis without evident common bile duct stone. METHODS: We studied 6 adult patients with a peculiar form of cholelithiasis. MDR3 gene sequence was determined by reverse-transcription polymerase chain reaction amplification of mononuclear cell RNAs followed by direct sequencing. Hepatic bile was analyzed in 2 patients. RESULTS: All patients shared the following features: at least 1 episode of biliary colic, pancreatitis, or cholangitis; biochemical evidence of chronic cholestasis; recurrence of symptoms after cholecystectomy; presence of echogenic material in the intrahepatic bile ducts; and prevention of recurrence by ursodeoxycholic acid therapy. Hepatic bile composition showed a high cholesterol/phospholipid ratio and cholesterol crystals. In all patients, we found MDR3 gene mutations involving a conserved amino acid region. CONCLUSIONS: These preliminary observations suggest that MDR3 gene mutations represent a genetic factor involved in this peculiar form of cholesterol gallstone disease in adults. They require further studies to assess the prevalence of MDR3 gene defects in symptomatic and silent cholesterol gallstone disease.
ATP Binding Cassette Transporter, Subfamily B↗
Musical processing in high functioning children with autism.
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Autistic Disorder↗
Differential HFE allele expression in hemochromatosis heterozygotes.
BACKGROUND & AIMS: Hereditary hemochromatosis is associated with C282Y homozygosity. Some heterozygotes may also present with abnormal iron parameters. However, the precise role of H63D and C282Y mutations in iron overload is poorly understood. We investigated the level of expression of the mutated and unmutated HFE alleles in these heterozygous patients. METHODS: We studied the expression of HFE messenger RNAs in peripheral blood mononuclear cells from 34 heterozygotes using reverse-transcription polymerase chain reaction (PCR) followed by enzymatic digestion or sequence analysis of the PCR products, which allows relative quantification of mutated and unmutated transcripts. HFE proteins were quantified by Western blotting in Epstein-Barr virus-immortalized lymphocyte extracts from 2 C282Y and H63D homozygotes and a compound heterozygote. RESULTS: (187C > G; H63D) mutated transcripts predominated in H63D and compound heterozygotes and the normal transcripts in C282Y heterozygotes. The amount of HFE protein was increased in the H63D homozygotes and the compound heterozygote compared with the C282Y homozygotes. In addition, we found a new mutation at codon 282 (C282S) associated with severe iron overload. CONCLUSIONS: We demonstrate the existence of differential allelic expression of the HFE alleles, suggesting that the (187C > G; H63D) mutation plays a role in the disease expression in H63D heterozygotes, in particular when associated with environmental or host factors.
Adult↗
A date to remember: the nature of memory in savant calendrical calculators.
BACKGROUND: Savant calendar calculators can supply with speed the day of the week of a given date. Although memory is suggested to be an important component of this unusual ability, memory function has never been systematically investigated in these skilled yet learning impaired individuals. METHODS: Eight savant calendrical calculators, most of whom had autism, were compared with eight verbal IQ, age and diagnosis matched controls on digit and word span tests and measures of long-term memory for words and calendrical information (individual years). In an analogue to the 'generation effect', the savants' memory for dates was also compared following calculation and study/read tasks. RESULTS: The savants did not differ from controls on measures of general short- and long-term memory. They did, however, show a clear recall superiority for the long-term retention of calendrical material. They also remembered calculated dates better than those that were only studied. CONCLUSIONS: A general mnemonic advantage cannot explain savant date calculation skills. Rather, through exposure to date information, the savants are suggested to develop a structured calendar-related knowledge base with the process of calculation utilizing the interrelations within this knowledge store. The cognitive processing style characteristic of autism may also play a role in the acquisition of this savant ability.
Adult↗
Can children with autistic spectrum disorders perceive affect in music? An experimental investigation.
BACKGROUND: Children with autistic spectrum disorders typically show impairments in processing affective information within social and interpersonal domains. It has yet to be established whether such difficulties persist in the area of music; a domain which is characteristically rich in emotional content. METHODS: Fourteen children with autism and Asperger syndrome and their age and intelligence matched controls were tested for their ability to identify the affective connotations of melodies in the major or minor musical mode. They were required to match musical fragments with schematic representations of happy and sad faces. RESULTS: The groups did not differ in their ability to ascribe the musical examples to the two affective categories. CONCLUSIONS: In contrast to their performance within social and interpersonal domains, children with autistic disorders showed no deficits in processing affect in musical stimuli.
Adolescent↗
A visually impaired savant artist: interacting perceptual and memory representations.
In this single case study, paintings by a visually impaired and cognitively handicapped savant artist are evaluated. He paints his pictures exclusively from memory, either after having looked at a natural scene through binoculars, or after studying landscape photographs in brochures, catalogues, and books. The paintings are compared with the models from which they were derived, and the resulting generative changes are accounted for by an interaction between impaired visual input and memory transformations.
Autistic Disorder↗
The pictorial context dependency of savant artists: a research note.
The relative immunity of the concept of size constancy in the face of changes to the retinal image as well as the pictorial device of linear perspective were investigated with 9 savant artists and 9 controls. For drawing use of pictorial rules seemed independent of levels of intelligence; however, when a construction instead of a drawing task had to be carried out, diagnosis rather than the presence or absence of talent was the decisive factor.
Adult↗
Enterocyte differentiation is compatible with SV40 large T expression and loss of p53 function in human colonic Caco-2 cells. Status of the pRb1 and pRb2 tumor suppressor gene products.
Transfer of the SV40 large-T (LT) oncogene into isolated human and murine intestinal epithelial cells induced alterations of the ultrastructural organization and polarization of the resulting immortalized cell lines. We now demonstrate that the functional expression of the SV40 LT antigen in Caco-2 cells did not alter phenotypic markers of differentiation, including expression of villin, sucrase-isomaltase, brush border and dome formation. As compared to parental cells, the transfected Caco-2 LT9 cells exhibited similar growth curves and no invasive properties in vitro. The major oncogenic function of the SV40 LT antigen in transfected Caco-2 cells is associated with reduced latency times necessary for the manifestation of tumors in athymic nude mice. The Caco-2 cell line contained deleted and mutant p53 alleles (stop codon in position 204) and has no detectable truncated p53 protein by Western blot. Molecular complexes between the SV40 LT antigen and the retinoblastoma-related proteins pRb1 and Rb2 were clearly identified at the different phases of the growth curve. When compared to normal human colonic crypts, Caco-2 cell differentiation is related to partial redistribution of pRb1 into hypophosphorylated, antiproliferative forms. The pRb2 protein is found elevated in a subset of human colorectal tumors and their corresponding liver metastases. We conclude that: (1) Caco-2 cells exert a dominant control against the oncogenic functions of the LT antigen; (2) loss of p53 function is not restrictive for the establishment of polarity and differentiation of the enterocyte lineage; (3) the levels and phosphorylation status of the Rb1 and Rb2 proteins may play important roles in the proliferation and differentiation of normal and neoplastic human colonic mucosa.
Animals↗
Overexpression of p53 mRNA in colorectal cancer and its relationship to p53 gene mutation.
We analysed the frequency of p53 mRNA overexpression in a series of 109 primary colorectal carcinomas and its association with p53 gene mutation, which has been correlated with short survival. Sixty-nine of the 109 cases (63%) demonstrated p53 mRNA overexpression, without any correlation with stage or site of disease. Comparison with p53 gene mutation indicated that, besides cases in which p53 gene mutation and p53 mRNA overexpression were either both present (40 cases) or both absent (36 cases), there were also cases in which p53 mRNA was overexpressed in the absence of any mutation (29 cases) and those with a mutant gene in which the mRNA was not overexpressed (four cases). Moreover, the mutant p53 tumours exhibited an increase of p53 mRNA expression, which was significantly higher in tumours expressing the mutated allele alone than in tumours expressing both wild- and mutated-type alleles. These data (1) show that p53 mRNA overexpression is a frequent event in colorectal tumours and is not predictive of the status of the gene, i.e. whether or not a mutation is present; (2) provide further evidence that p53 protein overexpression does not only result from an increase in the half-life of mutated p53 and suggest that inactivation of the p53 function in colorectal cancers involves at least two distinct mechanisms, including p53 overexpression and/or mutation; and (3) suggest that p53 mRNA overexpression is an early event, since it is not correlated with Dukes stage.
Colonic Neoplasms↗
Phenotypic expression in double heterozygotes for familial hypercholesterolemia and familial defective apolipoprotein B-100.
Variability in the expression of monogenic lipid disorders may be observed in patients carrying the same DNA mutation, suggesting possible genetic or environmental interactions. Our objective was to investigate the genotype-phenotype relationships in two unrelated French patients with an aggravated expression of a dominantly inherited hypercholesterolemia. In probands, segregation analysis complemented by DNA sequencing identified heterozygous defective alleles and mutations on two nonallelic loci for two monogenic lipid disorders: familial hypercholesterolemia at the low density lipoprotein (LDL) receptor locus and familial defective apolipoprotein B-100 at the locus encoding its ligand, apolipoprotein B-100. The LDL-receptor missense mutations had been reported in French Canadians. The apolipoprotein B mutation was the Arg3500Gln founder mutation in Northern Europe. Probands had an unusual phenotype of aggravated hypercholesterolemia that was complicated with premature coronary arterial disease, although remaining responsive to lipid-lowering drugs. This phenotype was distinct from that observed in their heterozygous relatives and distinct from those observed in FH or FDB homozygotes. These cases refer to a new class of patients with digenic lipid disorders, defined by specific clinical features that result from the combined effects of two independent loci. Moreover, the observed phenotype of aggravated hypercholesterolemia gives further evidence that receptor and ligand play distinct roles in regulating LDL metabolism. Although uncommon, these cases give insight into the molecular mechanisms that underly the clinical variability of inherited hypercholesterolemia.
Adult↗
A savant poet.
Poems by an individual with a diagnosis of Asperger's Syndrome were analysed and compared with those of a comparison poet. Though the savant poet performed less efficiently on formal language tests supposed to tap creativity, there were few differences between the two poets in regard to the poems' content and the use of various structural devices. The poems by the savant referred more often to aspects of self-analysis, while descriptions of people not related to the self were less frequent. Both poets made use of similes and metaphors. The results are discussed in terms of different modular domains within the language system.
Aptitude↗
Recurrent and novel LDL receptor gene mutations causing heterozygous familial hypercholesterolemia in La Habana.
The molecular basis of familial hypercholesterolemia (FH) in three families of Spanish descent from La Habana was investigated by the candidate gene approach. The Arg3500Gln mutation of apolipoprotein B-100 was not found. Identification of low density lipoprotein receptor (LDLR) gene haplotypes segregating with FH guided the characterisation of three point mutations by automated sequencing. One, a Val408-->Met missense mutation, a founder mutation in Afrikaner FH patients, was recurrent, being associated with a distinct DNA haplotype. The other two, Glu256-->Lys and Val776-->Met missense mutations, were novel and modified highly conserved residues. These mutations were absent in normolipidemic subjects and were associated in heterozygous carriers with twice the cholesterol levels observed in non-carriers. Noticeably, cardiovascular complications were rarely observed in older heterozygotes, even in those with the Afrikaner FH-2 mutation. These findings confirm the molecular heterogeneity of LDLR gene mutations causing FH and the variability of their expression across different populations.
Adolescent↗
Savants, segments, art and autism.
This study describes two experiments which investigate pattern construction by graphically gifted, autistic savants. We explore whether the notion of weak central coherence in autism might be extended to account for the relatively high frequency of savants among the autistic population. We also suggest that an awareness of constituent segments in wholes may be relevant to artistic talent in general.
Adolescent↗
Two autistic savant readers.
Two young autistic children of normal intelligence were tested repeatedly for their reading ability. Their comprehension was appropriate for their developmental status, however, they had reading speeds that were considerably faster than those of their age-matched normal controls. Randomizing word order, and thereby reducing meaningfulness, resulted in an equivalent reduction in relative reading speeds for the younger autistic subject and his control. For the older of the normal children, the effect of randomizing word order was very marked, whereas its effect was minimal for the older of the two autistic boys. The results are regarded as an indication that efficient grapheme-phoneme conversion is a modular component of the reading skill and this transcoding process is primarily responsible for the fast reading of the autistic children.
Aptitude↗
Visual and motor functions in graphically gifted savants.
Savant artists represent a conundrum to our understanding of the nature of high level specific talents as well as to the concept of general intellectual impairment. In the present paper, we are particularly concerned with the relationship between general perceptual-motor functions in relation to drawing aptitude. Drawing is by definition a perceptual-motor operation, yet mental handicap tends to be associated with some degree of impairment in this area. The following study seeks to isolate such aspects of performance on general perceptual-motor skills that might be associated with drawing ability, and may thus be regarded as building blocks underlying the manifestation of graphic talent. The results are discussed in terms of the relationships between graphic talent, non-verbal intelligence and visual-motor functions.
Adolescent↗
Preliminary results of Pneumocystis carinii strain differentiation by using molecular biology.
The mode of Pneumocystis carinii transmission is controversial. Recent studies point to exogenous inoculation rather than reactivation, and person-to-person transmission has also been suggested. Comparison of nucleotide sequences of the large-subunit mitochondrial rRNA gene of P. carinii from human immunodeficiency virus-seropositive patients showed strain differences.
AIDS-Related Opportunistic Infections↗
Phosphorylation of vimentin is an intermediate step in protein kinase C-mediated glycoconjugate secretion.
We have previously shown that fibroblasts from patients with cystic fibrosis (CF) display a higher response to 4 beta-phorbol 12-myristate 13-acetate (PMA) than control fibroblasts for stimulation of both protein kinase C (PKC) cytosol-to-membrane translocation and glycoconjugate secretion. In this study we took advantage of these cells with differential responsiveness to PMA to investigate the endogenous substrate(s) involved in PKC stimulation of glycoconjugate secretion after verification of cystic fibrosis transmembrane conductance regulator gene expression in control and CF fibroblasts. We show that a 57-kDa protein that was associated with cytoskeleton and was identified as vimentin by immunoblotting emerged as a good candidate for mediating PKC stimulation of glycoconjugate secretion. 1) Its phosphorylation by PMA was abolished by PKC inhibition or depletion. 2) In both control and CF fibroblasts, the PMA-induced increase in its phosphorylation preceded the phorbol ester stimulation of glycoconjugate secretion. 3) For both processes, the concentration-response curves were superimposable, with higher maximal levels for CF fibroblasts relative to controls. 4) PMA-stimulated 57-kDa protein phosphorylation, like PMA-stimulated glycoconjugate secretion, was significantly increased by Ca2+. 5) Increased PMA phosphorylation of the 57-kDa protein as a result of okadaic acid inhibition of intracellular phosphatases was reflected in increased PMA stimulation of glycoconjugate secretion. In conclusion, 1) PMA phosphorylation of a cytoskeletal 57-kDa protein, identified as vimentin, appears to be an intermediate step in PKC stimulation of constitutive glycoconjugate secretion in human skin fibroblasts; and 2) this process is impaired in CF disease.
Base Sequence↗