Differential effects by sex with Kmt5b loss

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Lysine methyl transferase 5B (KMT5B) is a newly identified risk gene for neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD) and intellectual disability (ID).
• The specific role of KMT5B in brain development and function remains largely unknown.
• Understanding KMT5B's function is crucial for elucidating NDD pathogenesis.

Purpose of the Study:

• To neurodevelopmentally characterize the effects of KMT5B haploinsufficiency in a mouse model.
• To assess behavioral and physical phenotypes associated with reduced KMT5B levels.
• To investigate potential sex-specific differences in KMT5B-related neurodevelopmental outcomes.

Main Methods:

• Utilized a Kmt5b gene-trap mouse line to create heterozygous (HET) mice.
• Administered a comprehensive neurodevelopmental test battery to WT and HET mice.
• Assessed reflexes, motor behavior, learning, memory, social behavior, repetitive movements, and anxiety-like behaviors in both male and female cohorts.

Main Results:

• HET mice exhibited microcephaly (smaller brain size) and reduced body weight and length, more pronounced in males.
• Neonatal HET males showed delayed eye opening and weaker reflexes.
• Adult HET mice displayed altered anxiety, depression, fear, and extinction learning, with sex-specific differences in repetitive grooming and thermal pain sensitivity.

Conclusions:

• KMT5B haploinsufficiency leads to significant neurodevelopmental and behavioral alterations in mice.
• These findings highlight KMT5B's critical role in brain development and function.
• The observed sex dimorphisms suggest KMT5B may contribute to the sex bias seen in human NDDs.