Heterozygous deletion of the Williams–Beuren syndrome critical interval in mice recapitulates most features of the human disorder

Abstract

Williams-Beuren syndrome is a developmental multisystemic disorder caused by a recurrent 1.55-1.83 Mb heterozygous deletion on human chromosome band 7q11.23. Through chromosomal engineering with the cre-loxP system, we have generated mice with an almost complete deletion (CD) of the conserved syntenic region on chromosome 5G2. Heterozygous CD mice were viable, fertile and had a normal lifespan, while homozygotes were early embryonic lethal. Transcript levels of most deleted genes were reduced 50% in several tissues, consistent with gene dosage. Heterozygous mutant mice showed postnatal growth delay with reduced body weight and craniofacial abnormalities such as small mandible. The cardiovascular phenotype was only manifested with borderline hypertension, mildly increased arterial wall thickness and cardiac hypertrophy. The neurobehavioral phenotype revealed impairments in motor coordination, increased startle response to acoustic stimuli and hypersociability. Mutant mice showed a general reduction in brain weight. Cellular and histological abnormalities were present in the amygdala, cortex and hippocampus, including increased proportion of immature neurons. In summary, these mice recapitulate most crucial phenotypes of the human disorder, provide novel insights into the pathophysiological mechanisms of the disease such as the neural substrates of the behavioral manifestations, and will be valuable to evaluate novel therapeutic approaches.

Cognitive deficits in mice lacking Nsun5, a cytosine‐5 RNA methyltransferase, with impairment of oligodendrocyte precursor cells

“…The whole-brain volume in patients with WBS has been reported to be reduced by 13% (Thompson et al, 2005). Heterozygous deletion from Gtf2i to Fkbp6 in mice caused a reduction in brain weight (Segura-Puimedon et al, 2014). In mice lacking Limk1 to Fkbp6, the brains are smaller than the brains of WT mice (Li et al, 2009).…”

“…The microdeletion disorder WBS is widely studied because of its unique cognitive/neuropsychiatric profile and distinct dysmorphic phenotype (Kaplan, Wang, & Francke, 2001). Heterozygous deletion from Gtf2i to Fkbp6 in mice causes deficits in spatial working memory and hippocampal synaptic function (Borralleras et al, 2016;Segura-Puimedon et al, 2014). Single-gene knockout mice for WBS deletion loci have been reported, including mice with a heterozygous Cyln2 deletion, which exhibits mild growth retardation, mild brain abnormality, attenuated synaptic plasticity, and motor function (Hoogenraad et al, 2002), and mice lacking Limk1 to Fkbp6, which show cognitive defects (Li et al, 2009).…”

Metabolic abnormalities in Williams–Beuren syndrome

“…When phenotypes of microdeletions are the result of interactive effects of the haploinsufficient genes, there may be compensatory effects with partial deletions absent in full deletions 20 38 39. In addition, the failure to show relevant phenotypes in mouse models with similar genotypes to humans underscores the physiological differences between mice and humans.…”

“…Four groups of mice were used, all bred on a majority C57BL/6J background (97%) (see online supplementary figure S1): complete deletion (CD) mice bearing a heterozygous 1.1 Mb deletion of the orthologous WBS locus from Gtf2i to Fkb6, 20 mice with approximately half deletions of the interval, called the distal deletion (DD) (0.67 Mb from Limk1 to Trim50 ) and the proximal deletion (PD) (0.45 Mb from Gtf2i to Limk1 ) , 21 and the wild-type (WT) littermates as controls. Tail clipping was performed within 4 weeks of birth to obtain DNA using standard protocols and determine the genotype by a Multiple Ligation-dependent Probe Amplification assay (primers22 in online supplementary table S2).…”

Functions of Gtf2i and Gtf2ird1 in the developing brain: transcription, DNA-binding, and long term behavioral consequences

“…Heterozygous and homozygous animals fell off a ledge sooner than WT littermates (p=0.0038, p=0.0007, respectively) (Figure 5A). Marble burying has not been reported in other Gtf2ird1 models, but in larger WS models that delete the entire syntenic WSCR or the proximal half of the region containing Gtf2ird1 have shown decreased marble burying in mutants (5, 36). We observed a similar significant effect of genotype on the number of marbles buried (F 2,80 =6.17, p =0.0033), with Gtf2ird1 -/- mutants burying fewer marbles than WT mice (p=0.002) (Figure 5B).…”