Differential effects by sex with Kmt5b loss.
KMT5B mutations produce ASD-like traits in mice, but the problems appear in sex-specific forms.
01Research in Context
What this study did
Scientists bred mice missing one copy of the Kmt5b gene. They watched how the pups grew, learned, and played. Boys and girls were scored separately to spot any sex gaps.
What they found
Half-dose Kmt5b gave both sexes learning and social hiccups. The problems looked a bit like human ASD plus ID. Yet the details differed: each sex showed its own set of weak spots.
How this fits with other research
Li et al. (2024) scanned kids and teens with ASD. Girls, not boys, showed tighter brain networks, matching the mouse hint that girls express risk differently.
Mulder et al. (2020) tracked human mothers. Low good-cholesterol plus high amino acids raised ASD odds, but only for baby boys. Again, sex steers the outcome.
James et al. (1981) first noticed autistic girls often had lower IQ and more affected relatives. Johnson et al. (2021) now give a gene-level reason for that old clue.
Why it matters
You now have solid mouse data that the same gene can hit boys and girls in separate ways. When you assess a child with KMT5B variants, write sex-specific goals. Watch social skills closer in girls, motor skills in boys, or vice-versa as your data show. Push for genetic reports that list sex; they will sharpen your treatment plan.
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02At a glance
03Original abstract
Lysine methyl transferase 5B (KMT5B) has been recently highlighted as a risk gene in genetic studies of neurodevelopmental disorders (NDDs), specifically, autism spectrum disorder (ASD) and intellectual disability (ID); yet, its role in the brain is not known. The goal of this work was to neurodevelopmentally characterize the effect(s) of KMT5B haploinsufficiency using a mouse model. A Kmt5b gene-trap mouse line was obtained from the Knockout Mouse Project. Wild type (WT) and heterozygous (HET) mice were subjected to a comprehensive neurodevelopmental test battery to assess reflexes, motor behavior, learning/memory, social behavior, repetitive movement, and common ASD comorbidities (obsessive compulsion, depression, and anxiety). Given the strong sex bias observed in the ASD patient population, we tested both a male and female cohort of animals and compared differences between genotypes and sexes. HET mice were significantly smaller than WT littermates starting at postnatal day 10 through young adulthood which was correlated with smaller brain size (i.e., microcephaly). This was more severe in males than females. HET male neonates also had delayed eye opening and significantly weaker reflexes than WT littermates. In young adults, significant differences between genotypes relative to anxiety, depression, fear, and extinction learning were observed. Interestingly, several sexually dimorphic differences were noted including increased repetitive grooming behavior in HET females and an increased latency to hot plate response in HET females versus a decreased latency in HET males. LAY SUMMARY: Lysine methyl transferase 5B (KMT5B) has been recently highlighted as a risk gene in neurodevelopmental disorders (NDDs), specifically, autism spectrum disorder (ASD) and intellectual disability (ID); yet its role in the brain is not known. Our study indicates that mice lacking one genomic copy of Kmt5b show deficits in neonatal reflexes, sociability, repetitive stress-induced grooming, changes in thermal pain sensing, decreased depression and anxiety, increased fear, slower extinction learning, and lower body weight, length, and brain size. Furthermore, several outcomes differed by sex, perhaps mirroring the sex bias in ASD.
Autism research : official journal of the International Society for Autism Research, 2021 · doi:10.1523/JNEUROSCI.5685-08.2009