Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY Kabuki Syndrome (KS) is a rare disease caused by heterozygous pathogenic mutations in two known genes: KDM6A (~20% cases) and KMT2D (~80% cases). Both genes are broadly expressed in many tissues and their activity spans temporally from development to postnatal adult life. KS patients present with various degrees of clinical abnormalities, including severe muscular hypotonia and reduced muscle strength. Whether hypotonia develops as a consequence of nerve conduction malfunction or it is due to a cell-autonomous primary defect in skeletal muscle is currently unknown. Further, skeletal muscle tissue from patients affected by KS has not been thoroughly studied. Our main hypothesis is that skeletal muscle tissue is primarily affected by mutations in KMT2D, which results in dysregulated muscle function. We propose to validate our hypothesis via the following specific Aims: 1) Define primary versus secondary muscle function defects using constitutive and conditional mouse models of KS; 2) Determine the gene networks and molecular targets of KMT2D driving muscle hypotonia in constitutive and conditional KS mouse models; 3) Define muscle satellite cell heterogeneity and `immaturity' in conditional and constitutive KS models, as well as in human patients. The work proposed will fill major gaps in our lack of knowledge about etiology of hypotonia in Kabuki syndrome and will pave the way for clinical improvements of patient care.
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