Mouse model sheds light on malnutrition in Down syndrome
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US researchers have identified a mouse model of Down syndrome that might be suitable for studying nutritional deficiencies in the disorder. Until now, there has been little scientific evidence to support paediatricians’ and parents’ suspicions that children with Down syndrome tend to be malnourished. The mouse model, known as Ts65Dn, is trisomic for a segment of murine chromosome 16 that is syntenic with a critical region of human chromosome 21 (q22) – the chromosome that is trisomic in people with Down syndrome. Often, lack of synteny means that mouse models of human multigene disorders are difficult to find. However, at least 21 genes are conserved between mouse chromosome 16 and human chromosome 21q. ‘These similarities make the Ts65Dn mouse a good potential model for Down syndrome’, says James Croom, Professor of Nutrition and Physiology at North Carolina State University (Raleigh, NC, USA), whose group has been studying the nutritional status of Ts65Dn mice. These mice have been used for years to investigate how Down syndrome affects neurological function, but until now no one knew they could also be used to study nutrition and metabolism. ‘The extra chromosome that causes Down syndrome is associated with metabolic changes’, says Croom, whose team compared jejunal function and plasma amino acid concentrations in Ts65Dn mice and their non-trisomic littermates [Cefalu, J.A. et al. (1998) Growth, Dev. Aging 62, 47–59]. ‘It is highly likely that affected children have different nutrient needs and that their ability to absorb nutrients from food is impaired. Our failure to address these special nutrition needs might compromise their general health. We need to find out if these changes are reversible.’ In the experiments, Tn65Dn mice weighed the same as control mice at birth, and they ate just as much. However, by around 2.75 months their body weight was significantly lower than that of controls, whether they had been given a constant supply of food or had been deprived of food for 16 hours. This suggests that there might be differences in postnatal metabolism or nutrient absorption between the two groups, although the trisomic mice were also four times as active as controls, as measured by the number of times a horizontal light-grid was broken during a 12-minute measurement period. The authors suggest that this hyperactivity probably leads to increased futile energy expenditure, although this was not fully quantified in the study. Jejunal histomorphometry showed shorter villus height and decreased villus planar circumference in Ts65Dn mice compared with controls. As changes in villus architecture can be associated with malabsorption of nutrients, including monosaccharides, Croom’s group studied glucose absorption but found no significant difference between trisomic mice and controls. However, in vitro tests showed that trisomic mice expended up to 20% more metabolic energy than controls to absorb nutrients from glucose. ‘We also found that trisomic mice had a clear derangement in the way they metabolised protein’, says Croom. All these findings line up very well with the few clinical studies that have been done, he adds. Compared with controls, the Ts65Dn mice had significantly higher plasma concentrations of valine (44.3%), leucine (38.7%), isoleucine (34.5%) and phenylalanine (25.8%). Concentrations of leucine, isoleucine and phenylalanine are also significantly raised in patients with Down syndrome, as are cysteine concentrations. However, the significance of these results remains unclear. Concentrations of citrulline – which is involved in the synthesis of arginine, an amino acid important for growth – were also higher in Ts65Dn mice. This finding, the authors suggest, could mean that the extra genomic material results in enhanced protein turnover and thus a greater need for arginine synthesis. The authors believe that Ts65Dn mice are a useful model for the study of digestion, absorption and metabolism in Down syndrome. Decreased villus histomorphometric dimensions, decreased small intestine length, and higher metabolic energy expenditure for active glucose uptake in the jejunum all suggest intestinal absorptive and postabsorptive metabolic anomalies in Ts65Dn mice that are likely to alter growth, say the authors. The digestive and metabolic anomalies in Ts65Dn mice, Croom suggests, might have some relationship to the developmental abnormalities of Down syndrome. Croom has no immediate plans to identify the genes that cause increased energy costs and impaired absorption. ‘We are still trying to characterize the model’, he explains. The next stage will be to superimpose treatment with peptide YY (a member of the pancreatic polypeptide family that inhibits gastrointestinal motility and stimulates feeding) on the present study to enhance absorption. If this works in trisomic mice it could be tried in patients with Down syndrome. Croom is also working with North Carolina State colleague Jerry Spears to investigate aluminium absorption in Ts65Dn mice. People with Down syndrome develop Alzheimer’s disease by their 30s or early 40s, says Croom. ‘Since medical studies have shown a potential link between aluminium absorption and Alzheimer’s development, we want to study it in these mice.’ Dorothy Bonn 414 N e w s MOLECULAR MEDICINE TODAY, OCTOBER 1998 Copyright ©1998 Elsevier Science Ltd. All rights reserved. 1357 - 4310/98/$19.00 Mouse model sheds light on malnutrition in Down syndrome 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 XX Karyotype of a human with trisomy 21. Reproduced, with permission, from the Cyrogenetics Gallery, Dept of Pathology, University of Washington, Seattle, WA, USA(http://www.pathology.washington.edu/Cytogallery/). With thanks to David Adler.
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Transcript of Mouse model sheds light on malnutrition in Down syndrome
US researchers have identified amouse model of Down syndromethat might be suitable for studyingnutritional deficiencies in thedisorder. Until now, there has beenlittle scientific evidence to supportpaediatricians’ and parents’suspicions that children with Downsyndrome tend to be malnourished.
The mouse model, known asTs65Dn, is trisomic for a segmentof murine chromosome 16 that issyntenic with a critical region ofhuman chromosome 21 (q22) – thechromosome that is trisomic inpeople with Down syndrome.Often, lack of synteny means thatmouse models of human multigenedisorders are difficult to find.However, at least 21 genes areconserved between mousechromosome 16 and humanchromosome 21q. ‘Thesesimilarities make the Ts65Dnmouse a good potential model forDown syndrome’, says JamesCroom, Professor of Nutrition andPhysiology at North Carolina State University(Raleigh, NC, USA), whose group has beenstudying the nutritional status of Ts65Dn mice.These mice have been used for years toinvestigate how Down syndrome affectsneurological function, but until now no one knewthey could also be used to study nutrition andmetabolism.
‘The extra chromosome that causes Downsyndrome is associated with metabolic changes’,says Croom, whose team compared jejunalfunction and plasma amino acid concentrations inTs65Dn mice and their non-trisomic littermates[Cefalu, J.A. et al. (1998) Growth, Dev. Aging 62,47–59]. ‘It is highly likely that affected childrenhave different nutrient needs and that their abilityto absorb nutrients from food is impaired. Ourfailure to address these special nutrition needsmight compromise their general health. We needto find out if these changes are reversible.’
In the experiments, Tn65Dn mice weighedthe same as control mice at birth, and they atejust as much. However, by around 2.75 monthstheir body weight was significantly lower thanthat of controls, whether they had been given aconstant supply of food or had been deprived offood for 16 hours. This suggests that theremight be differences in postnatal metabolism or
nutrient absorption between the two groups,although the trisomic mice were also four timesas active as controls, as measured by the numberof times a horizontal light-grid was brokenduring a 12-minute measurement period. Theauthors suggest that this hyperactivity probablyleads to increased futile energy expenditure,although this was not fully quantified in thestudy.
Jejunal histomorphometry showed shortervillus height and decreased villus planarcircumference in Ts65Dn mice compared withcontrols. As changes in villus architecture can beassociated with malabsorption of nutrients,including monosaccharides, Croom’s groupstudied glucose absorption but found nosignificant difference between trisomic mice andcontrols. However, in vitro tests showed thattrisomic mice expended up to 20% moremetabolic energy than controls to absorbnutrients from glucose.
‘We also found that trisomic mice had a clearderangement in the way they metabolisedprotein’, says Croom. All these findings line upvery well with the few clinical studies that havebeen done, he adds. Compared with controls, theTs65Dn mice had significantly higher plasmaconcentrations of valine (44.3%), leucine
(38.7%), isoleucine (34.5%) andphenylalanine (25.8%).Concentrations of leucine, isoleucineand phenylalanine are alsosignificantly raised in patients withDown syndrome, as are cysteineconcentrations. However, thesignificance of these results remainsunclear.
Concentrations of citrulline –which is involved in the synthesis ofarginine, an amino acid important forgrowth – were also higher in Ts65Dnmice. This finding, the authorssuggest, could mean that the extragenomic material results in enhancedprotein turnover and thus a greaterneed for arginine synthesis.
The authors believe that Ts65Dnmice are a useful model for the studyof digestion, absorption andmetabolism in Down syndrome.Decreased villus histomorphometricdimensions, decreased smallintestine length, and highermetabolic energy expenditure foractive glucose uptake in the jejunum
all suggest intestinal absorptive andpostabsorptive metabolic anomalies in Ts65Dnmice that are likely to alter growth, say theauthors. The digestive and metabolic anomaliesin Ts65Dn mice, Croom suggests, might havesome relationship to the developmentalabnormalities of Down syndrome.
Croom has no immediate plans to identify thegenes that cause increased energy costs andimpaired absorption. ‘We are still trying tocharacterize the model’, he explains. The nextstage will be to superimpose treatment withpeptide YY (a member of the pancreaticpolypeptide family that inhibits gastrointestinalmotility and stimulates feeding) on the presentstudy to enhance absorption. If this works intrisomic mice it could be tried in patients withDown syndrome.
Croom is also working with North CarolinaState colleague Jerry Spears to investigatealuminium absorption in Ts65Dn mice. Peoplewith Down syndrome develop Alzheimer’s diseaseby their 30s or early 40s, says Croom. ‘Sincemedical studies have shown a potential linkbetween aluminium absorption and Alzheimer’sdevelopment, we want to study it in these mice.’
Dorothy Bonn
414
N e w s MOLECULAR MEDICINE TODAY, OCTOBER 1998
Copyright ©1998 Elsevier Science Ltd. All rights reserved. 1357 - 4310/98/$19.00
Mouse model sheds light on malnutrition in Down syndrome
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Karyotype of a human with trisomy 21. Reproduced, with permission, from the Cyrogenetics Gallery, Dept ofPathology, University of Washington, Seattle, WA, USA (http://www.pathology.washington.edu/Cytogallery/).With thanks to David Adler.
