TY - JOUR
T1 - Graded loss of tuberin in an allelic series of brain models of TSC correlates with survival, and biochemical, histological and behavioral features
AU - Yuan, Elizabeth
AU - Tsai, Peter T.
AU - Greene-colozzi, Emily
AU - Sahin, Mustafa
AU - Kwiatkowski, David J.
AU - Malinowska, Izabela A.
N1 - Funding Information:
This work was supported by National Institutes of Health (1P01NS24279-16, 2R37NS031535-14). P.T.T. received support from the Developmental Neurology Training Grant (T32 NS007473), American Academy of Neurology and the Nancy Lurie Marks Family Foundation. M.S. was supported by the John Merck Scholars Fund and the Children’s Hospital Boston Translational Research Program.
PY - 2012/10
Y1 - 2012/10
N2 - Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder with prominent brain manifestations due to mutations in either TSC1 or TSC2. Here, we describe novel mouse brain models of TSC generated using conditional hypomorphic and null alleles of Tsc2 combined with the neuron-specific synapsin I cre (SynIcre) allele. This allelic series of homozygous conditional hypomorphic alleles (Tsc2c-del3/c-del3SynICre+) and heterozygote null/conditional hypomorphic alleles (Tsc2k/c-del3SynICre+) achieves a graded reduction in expression of Tsc2 in neurons in vivo. The mice demonstrate a progressive neurologic phenotype including hunchback, hind limb clasp, reduced survival and brain and cortical neuron enlargement that correlates with a graded reduction in expression of Tsc2 in the two sets of mice. Both models also showed behavioral abnormalities in anxiety, social interaction and learning assays, which correlated with Tsc2 protein levels as well. The observations demonstrate that there are graded biochemical, cellular and clinical/behavioral effects that are proportional to the extent of reduction in Tsc2 expression in neurons. Further, they suggest that some patients with milder manifestations of TSC may be due to persistent low-level expression of functional protein from their mutant allele. In addition, they point to the potential clinical benefit of strategies to raise TSC2 protein expression from the wild-type allele by even modest amounts.
AB - Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder with prominent brain manifestations due to mutations in either TSC1 or TSC2. Here, we describe novel mouse brain models of TSC generated using conditional hypomorphic and null alleles of Tsc2 combined with the neuron-specific synapsin I cre (SynIcre) allele. This allelic series of homozygous conditional hypomorphic alleles (Tsc2c-del3/c-del3SynICre+) and heterozygote null/conditional hypomorphic alleles (Tsc2k/c-del3SynICre+) achieves a graded reduction in expression of Tsc2 in neurons in vivo. The mice demonstrate a progressive neurologic phenotype including hunchback, hind limb clasp, reduced survival and brain and cortical neuron enlargement that correlates with a graded reduction in expression of Tsc2 in the two sets of mice. Both models also showed behavioral abnormalities in anxiety, social interaction and learning assays, which correlated with Tsc2 protein levels as well. The observations demonstrate that there are graded biochemical, cellular and clinical/behavioral effects that are proportional to the extent of reduction in Tsc2 expression in neurons. Further, they suggest that some patients with milder manifestations of TSC may be due to persistent low-level expression of functional protein from their mutant allele. In addition, they point to the potential clinical benefit of strategies to raise TSC2 protein expression from the wild-type allele by even modest amounts.
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U2 - 10.1093/hmg/dds262
DO - 10.1093/hmg/dds262
M3 - Article
C2 - 22752306
AN - SCOPUS:84866354915
SN - 0964-6906
VL - 21
SP - 4286
EP - 4300
JO - Human molecular genetics
JF - Human molecular genetics
IS - 19
M1 - dds262
ER -