Lysinuric protein intolerance (LPI, MIM 222700) is an autosomal recessive defect of cationic amino acids transport at the basolateral membrane of epithelial cells in the intestine and kidney, caused by mutations of the SLC7A7 gene.The unknown pathogenesis of the multisystem involvement of LPI, which includes a life-threatening alveolar proteinosis, and the lack of an effective treatment has prompted the creation of a LPI animal model. A constitutive knockout of Slc7a7 was generated by random insertional mutagenesis in embryonic stem cells (Lexicon Genetics Inc, Texas). More than 400 Slc7a7+/- intercrosses led to only one Slc7a7-/- live male. Since birth, this null animal showed a severe failure to thrive compared to siblings. The null animal, still alive at 12 months of age, shows also a strong reduced fertility compared with +/- and +/+ littermates. It is currently fed on a low protein diet and citrulline supplementation. Five additional Slc7a7-/- died within the first day of life, all showing severe growth failure. To establish the timing of the apparent lethality of Slc7a7-/- mice, embryos were collected at E 16.5 and E 18.5 stages, respectively. The proportions of Slc7a7 genotypes were found as expected for an autosomal recessive transmission. These data suggest that Slc7a7-/- pups die early in the perinatal period and not during the embryogenesis. Most of Slc7a7-/- pups were probably lost at birth because of cannibalism. At E 16.5 stage, the Slc7a7-/- embryos were already smaller than +/- or +/+ sibs. None of the null embryos showed gross morphological abnormalities. In humans, LPI does not cause clinical manifestations until weaning is started, neither increased rate of spontaneous abortion is known. In mice the absence of Slc7a7 gene might cause an early severe metabolic derangement underlying the intrauterine growth failure.

A Slc7a7 null mouse model of lysinuric protein intolerance / M. P., Sperandeo; V., Ammendola; V., Fiorito; A., Pepe; M., D'Armiento; R., Vecchione; G., Andria; G., Borsani; Marigo, Valeria; S., Banfi; A., Ballabio; G. A., Sebastio. - In: AMERICAN JOURNAL OF HUMAN GENETICS. - ISSN 0002-9297. - STAMPA. - 73:(2003), pp. 444-444. ((Intervento presentato al convegno The American Society of Human Genetics 53rd Annual Meeting tenutosi a Los Angeles, USA nel 4-8 Novembre 2003.

A Slc7a7 null mouse model of lysinuric protein intolerance.

MARIGO, Valeria;
2003

Abstract

Lysinuric protein intolerance (LPI, MIM 222700) is an autosomal recessive defect of cationic amino acids transport at the basolateral membrane of epithelial cells in the intestine and kidney, caused by mutations of the SLC7A7 gene.The unknown pathogenesis of the multisystem involvement of LPI, which includes a life-threatening alveolar proteinosis, and the lack of an effective treatment has prompted the creation of a LPI animal model. A constitutive knockout of Slc7a7 was generated by random insertional mutagenesis in embryonic stem cells (Lexicon Genetics Inc, Texas). More than 400 Slc7a7+/- intercrosses led to only one Slc7a7-/- live male. Since birth, this null animal showed a severe failure to thrive compared to siblings. The null animal, still alive at 12 months of age, shows also a strong reduced fertility compared with +/- and +/+ littermates. It is currently fed on a low protein diet and citrulline supplementation. Five additional Slc7a7-/- died within the first day of life, all showing severe growth failure. To establish the timing of the apparent lethality of Slc7a7-/- mice, embryos were collected at E 16.5 and E 18.5 stages, respectively. The proportions of Slc7a7 genotypes were found as expected for an autosomal recessive transmission. These data suggest that Slc7a7-/- pups die early in the perinatal period and not during the embryogenesis. Most of Slc7a7-/- pups were probably lost at birth because of cannibalism. At E 16.5 stage, the Slc7a7-/- embryos were already smaller than +/- or +/+ sibs. None of the null embryos showed gross morphological abnormalities. In humans, LPI does not cause clinical manifestations until weaning is started, neither increased rate of spontaneous abortion is known. In mice the absence of Slc7a7 gene might cause an early severe metabolic derangement underlying the intrauterine growth failure.
73
444
444
M. P., Sperandeo; V., Ammendola; V., Fiorito; A., Pepe; M., D'Armiento; R., Vecchione; G., Andria; G., Borsani; Marigo, Valeria; S., Banfi; A., Ballabio; G. A., Sebastio
A Slc7a7 null mouse model of lysinuric protein intolerance / M. P., Sperandeo; V., Ammendola; V., Fiorito; A., Pepe; M., D'Armiento; R., Vecchione; G., Andria; G., Borsani; Marigo, Valeria; S., Banfi; A., Ballabio; G. A., Sebastio. - In: AMERICAN JOURNAL OF HUMAN GENETICS. - ISSN 0002-9297. - STAMPA. - 73:(2003), pp. 444-444. ((Intervento presentato al convegno The American Society of Human Genetics 53rd Annual Meeting tenutosi a Los Angeles, USA nel 4-8 Novembre 2003.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/797715
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