scholarly journals A novel mouse model of creatine transporter deficiency

F1000Research ◽  
2015 ◽  
Vol 3 ◽  
pp. 228
Author(s):  
Laura Baroncelli ◽  
Maria Grazia Alessandrì ◽  
Jonida Tola ◽  
Elena Putignano ◽  
Martina Migliore ◽  
...  
Keyword(s):  
Mouse Model ◽  
Murine Model ◽  
Deficiency Syndrome ◽  
Speech Impairment ◽  
Behavioral Disturbances ◽  
Creatine Transporter ◽  
Creatine Transporter Deficiency ◽  
Creatine Deficiency ◽  
Creatine Deficiency Syndrome ◽  
Transporter Deficiency

Mutations in the creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CCDS1), an X-linked metabolic disorder characterized by cerebral Cr deficiency causing intellectual disability, seizures, movement  and behavioral disturbances, language and speech impairment ( OMIM #300352).CCDS1 is still an untreatable pathology that can be very invalidating for patients and caregivers. Only two murine models of CCDS1, one of which is an ubiquitous knockout mouse, are currently available to study the possible mechanisms underlying the pathologic phenotype of CCDS1 and to develop therapeutic strategies. Given the importance of validating phenotypes and efficacy of promising treatments in more than one mouse model we have generated a new murine model of CCDS1 obtained by ubiquitous deletion of 5-7 exons in the Slc6a8 gene. We showed a remarkable Cr depletion in the murine brain tissues and cognitive defects, thus resembling the key features of human CCDS1. These results confirm that CCDS1 can be well modeled in mice. This CrT−/y murine model will provide a new tool for increasing the relevance of preclinical studies to the human disease.

scholarly journals A novel mouse model of creatine transporter deficiency

F1000Research ◽  
2014 ◽  
Vol 3 ◽  
pp. 228 ◽  
Author(s):  
Laura Baroncelli ◽  
Maria Grazia Alessandrì ◽  
Jonida Tola ◽  
Elena Putignano ◽  
Martina Migliore ◽  
...  
Keyword(s):  
Mouse Model ◽  
Murine Model ◽  
Deficiency Syndrome ◽  
Speech Impairment ◽  
Behavioral Disturbances ◽  
Creatine Transporter ◽  
Creatine Transporter Deficiency ◽  
Creatine Deficiency ◽  
Creatine Deficiency Syndrome ◽  
Transporter Deficiency

Mutations in the creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CCDS1), an X-linked metabolic disorder characterized by cerebral Cr deficiency causing intellectual disability, seizures, movement  and behavioral disturbances, language and speech impairment ( OMIM #300352).CCDS1 is still an untreatable pathology that can be very invalidating for patients and caregivers. Only two murine models of CCDS1, one of which is an ubiquitous knockout mouse, are currently available to study the possible mechanisms underlying the pathologic phenotype of CCDS1 and to develop therapeutic strategies. Given the importance of validating phenotypes and efficacy of promising treatments in more than one mouse model we have generated a new murine model of CCDS1 obtained by ubiquitous deletion of 5-7 exons in the Slc6a8 gene. We showed a remarkable Cr depletion in the murine brain tissues and cognitive defects, thus resembling the key features of human CCDS1. These results confirm that CCDS1 can be well modeled in mice. This CrT−/y murine model will provide a new tool for increasing the relevance of preclinical studies to the human disease.

scholarly journals Rescue by 4-phenylbutyrate of several misfolded creatine transporter-1 variants linked to the creatine transporter deficiency syndrome

2019 ◽  
Vol 161 ◽  
pp. 107572 ◽  
Author(s):  
Ali El-Kasaby ◽  
Ameya Kasture ◽  
Florian Koban ◽  
Matej Hotka ◽  
Hafiz M.M. Asjad ◽  
...  
Keyword(s):  
Deficiency Syndrome ◽  
Creatine Transporter ◽  
Creatine Transporter Deficiency ◽  
Transporter Deficiency

scholarly journals A new rat model of creatine transporter deficiency reveals behavioral disorder and altered brain metabolism

2020 ◽  
Author(s):  
Lara Duran-Trio ◽  
Gabriella Fernandes-Pires ◽  
Dunja Simicic ◽  
Jocelyn Grosse ◽  
Clothilde Roux ◽  
...  
Keyword(s):  
Point Mutation ◽  
Rat Model ◽  
Energy Demand ◽  
High Energy ◽  
Behavioral Disorder ◽  
Creatine Transporter ◽  
Efficient Treatment ◽  
Creatine Transporter Deficiency ◽  
Creatine Deficiency ◽  
Transporter Deficiency

ABSTRACTCreatine is an organic compound used as fast phosphate energy buffer to recycle ATP, important in tissues with high energy demand such as muscle or brain. Creatine is taken from the diet or endogenously synthetized by the enzymes AGAT and GAMT, and specifically taken up by the transporter SLC6A8. Deficit in the endogenous synthesis or in the transport leads to Cerebral Creatine Deficiency Syndromes (CCDS). CCDS are characterized by brain creatine deficiency, intellectual disability with severe speech delay, behavioral troubles such as attention deficits and/or autistic features, and epilepsy. Among CCDS, the X-linked creatine transporter deficiency (CTD) is the most prevalent with no efficient treatment so far. Different mouse models of CTD were generated by doing long deletions in the Slc6a8 gene showing reduced brain creatine and cognitive deficiencies or impaired motor function. We present a new knock-in (KI) rat model of CTD holding an identical point mutation found in patients with reported lack of transporter activity. KI males showed brain creatine deficiency, increased urinary creatine/creatinine ratio, cognitive deficiency and autistic features. Slc6a8xY389C KI rat fairly enriches the spectrum of CTD models and provides new data about the pathology, being the first animal model of CTD carrying a point mutation.

scholarly journals Cyclocreatine treatment ameliorates the cognitive, autistic and epileptic phenotype in a mouse model of Creatine Transporter Deficiency

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Francesco Cacciante ◽  
Mariangela Gennaro ◽  
Giulia Sagona ◽  
Raffaele Mazziotti ◽  
Leonardo Lupori ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Therapeutic Benefit ◽  
Behavioral Disturbances ◽  
Creatine Transporter ◽  
Chemically Modified ◽  
Eeg Abnormalities ◽  
Creatine Transporter Deficiency ◽  
Novel Biomarkers ◽  
Transporter Deficiency ◽  
Potential Therapeutic Benefit

Abstract Creatine Transporter Deficiency (CTD) is an inborn error of metabolism presenting with intellectual disability, behavioral disturbances and epilepsy. There is currently no cure for this disorder. Here, we employed novel biomarkers for monitoring brain function, together with well-established behavioral readouts for CTD mice, to longitudinally study the therapeutic efficacy of cyclocreatine (cCr) at the preclinical level. Our results show that cCr treatment is able to partially correct hemodynamic responses and EEG abnormalities, improve cognitive deficits, revert autistic-like behaviors and protect against seizures. This study provides encouraging data to support the potential therapeutic benefit of cyclocreatine or other chemically modified lipophilic analogs of Cr.

X-linked creatine deficiency syndrome: A novel mutation in creatine transporter geneSLC6A8

2002 ◽  
Vol 52 (2) ◽  
pp. 227-231 ◽  
Author(s):  
Alberto Bizzi ◽  
Marianna Bugiani ◽  
Gajja S. Salomons ◽  
Donald H. Hunneman ◽  
Isabella Moroni ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Deficiency Syndrome ◽  
Creatine Transporter ◽  
Creatine Deficiency ◽  
Creatine Deficiency Syndrome
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