TY - JOUR
T1 - Two hypomorphic alleles of mouse Ass1 as a new animal model of citrullinemia type I and other hyperammonemic syndromes
AU - Perez, Carlos J.
AU - Jaubert, Jean
AU - Gueacute, Jean Louis
AU - Barnhart, Kirstin F.
AU - Ross-Inta, Catherine M.
AU - Quintanilla, Vicente C.
AU - Aubin, Isabelle
AU - Brandon, Jimi L.
AU - Otto, Nancy W.
AU - DiGiovanni, John
AU - Gimenez-Conti, Irma
AU - Giulivi, Cecilia
AU - Kusewitt, Donna F.
AU - Conti, Claudio J.
AU - Benavides, Fernando
N1 - Funding Information:
Supported by National Institutes of Health grant CA90922 (C.J.C.) ; Department of Health and Human Services/National Cancer Institute grants P30 CA016672 (F.B. and D.F. K.) and P30 ES007784 (I.G.C.) ; and funding from Autism Speaks (C.G.).
PY - 2010/10
Y1 - 2010/10
N2 - Citrullinemia type I (CTLN1, OMIM# 215700) is an inherited urea cycle disorder that is caused by an argininosuccinate synthetase (ASS) enzyme deficiency. In this report, we describe two spontaneous hypomorphic alleles of the mouse Ass1 gene that serve as an animal model of CTLN1. These two independent mouse mutant alleles, also described in patients affected with CTLN1, interact to produce a range of phenotypes. While some mutant mice died within the first week after birth, others survived but showed severe retardation during postnatal development as well as alopecia, lethargy, and ataxia. Notable pathological findings were similar to findings in human CTLN1 patients and included citrullinemia and hyperammonemia along with delayed cerebellar development, epidermal hyperkeratosis, and follicular dystrophy. Standard treatments for CTLN1 were effective in rescuing the phenotype of these mutant mice. Based on our studies, we propose that defective cerebellar granule cell migration secondary to disorganization of Bergmann glial cell fibers cause cerebellar developmental delay in the hyperammonemic and citrullinemic brain, pointing to a possible role for nitric oxide in these processes. These mouse mutations constitute a suitable model for both mechanistic and preclinical studies of CTLN1 and other hyperammonemic encephalopathies and, at the same time, underscore the importance of complementing knockout mutations with hypomorphic mutations for the generation of animal models of human genetic diseases.
AB - Citrullinemia type I (CTLN1, OMIM# 215700) is an inherited urea cycle disorder that is caused by an argininosuccinate synthetase (ASS) enzyme deficiency. In this report, we describe two spontaneous hypomorphic alleles of the mouse Ass1 gene that serve as an animal model of CTLN1. These two independent mouse mutant alleles, also described in patients affected with CTLN1, interact to produce a range of phenotypes. While some mutant mice died within the first week after birth, others survived but showed severe retardation during postnatal development as well as alopecia, lethargy, and ataxia. Notable pathological findings were similar to findings in human CTLN1 patients and included citrullinemia and hyperammonemia along with delayed cerebellar development, epidermal hyperkeratosis, and follicular dystrophy. Standard treatments for CTLN1 were effective in rescuing the phenotype of these mutant mice. Based on our studies, we propose that defective cerebellar granule cell migration secondary to disorganization of Bergmann glial cell fibers cause cerebellar developmental delay in the hyperammonemic and citrullinemic brain, pointing to a possible role for nitric oxide in these processes. These mouse mutations constitute a suitable model for both mechanistic and preclinical studies of CTLN1 and other hyperammonemic encephalopathies and, at the same time, underscore the importance of complementing knockout mutations with hypomorphic mutations for the generation of animal models of human genetic diseases.
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U2 - 10.2353/ajpath.2010.100118
DO - 10.2353/ajpath.2010.100118
M3 - Article
C2 - 20724589
AN - SCOPUS:77957326031
SN - 0002-9440
VL - 177
SP - 1958
EP - 1968
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 4
ER -