DeLeon, V. B. | Search bioRxiv

bioRxiv2024

In-utero rescue of neurological dysfunction in a mouse model of Wiedemann-Steiner syndrome

Wiedemann-Steiner syndrome (WDSTS) is a rare genetic cause of intellectual disability primarily caused by heterozygous loss of function variants in the gene encoding the histone methyltransferase KMT2A. Prior studies have shown successful postnatal amelioration of disease phenotypes for Rett, Rubinstein-Taybi and Kabuki syndromes, related Mendelian disorders of the epigenetic machinery. To explore whether the neurological phenotype in WDSTS is treatable in-utero, we created a novel mouse model carrying a loss of function variant in between two loxP sites. Kmt2a+/LSL mice demonstrate core features of WDSTS including growth retardation, craniofacial abnormalities, and hypertrichosis as well as hippocampal memory defects. The neurological phenotypes show rescue upon restoration of KMT2A in-utero following breeding to a nestin-Cre. Together, our data provide a novel mouse model to explore the therapeutic window in WDSTS. Our work suggests that WDSTS has a window of opportunity extending at least until the mid-point of in-utero development, making WDSTS an ideal candidate for future therapeutic strategies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/604339v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1b913caorg.highwire.dtl.DTLVardef@1c23ce3org.highwire.dtl.DTLVardef@12b8a25org.highwire.dtl.DTLVardef@17a9a4e_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

genetics↗

bioRxiv2019

Precocious Chondrocyte Differentiation Disrupts Skeletal Growth in Kabuki Syndrome Mice

Kabuki syndrome 1 (KS1) is a Mendelian disorder of the epigenetic machinery caused by mutations in the gene encoding KMT2D, which methylates lysine 4 on histone H3 (H3K4). KS1 is characterized by intellectual disability, postnatal growth retardation, and distinct craniofacial dysmorphisms. A mouse model (Kmt2d+/ {beta} Geo) exhibits features of the human disorder and has provided insight into other phenotypes; however, the mechanistic basis of skeletal abnormalities and growth retardation remains elusive. Using high-resolution micro-computed tomography we show that Kmt2d+/{beta}Geo mice have shortened long bones and ventral bowing of skulls. In vivo expansion of growth plates within both the skull and long bones suggests disrupted endochondral ossification as a common disease mechanism. Stable chondrocyte cell lines harboring inactivating mutations in Kmt2d exhibit increased proliferation and differentiation, which further supports this mechanism. A known inducer of chondrogenesis, SOX9, and its targets show markedly increased expression in Kmt2d-/- chondrocytes. By transcriptome profiling, we identify Shox2 as a putative KMT2D target. We propose that decreased KMT2D-mediated H3K4me3 at Shox2 releases Sox9 inhibition and thereby leads to enhanced chondrogenesis, providing a novel and plausible explanation for precocious chondrocyte differentiation. Our findings not only provide insight into the pathogenesis of growth retardation in KS1, but also suggest novel therapeutic targets to rescue growth retardation in KS1 and related disorders.

genetics↗