X-linked SYTL4 missense variant disrupts RAB27A-dependent vesicle trafficking and synaptic transmission in autism

31/07/2026

AI Summary

Recurrent hemizygous SYTL4 R126H variant in four males and a de novo RAB27A T41A variant implicate these genes in X-linked ASD.
R126H knock-in male mice show ASD-relevant behavioural abnormalities and synaptic deficits in medial prefrontal cortex.
SYTL4 and RAB27A variants disrupt their interaction, impair RAB27A-dependent vesicle trafficking and synaptic transmission.

AI Summary

We report a recurrent hemizygous missense variant, R126H, located within the Rab-binding domain of SYTL4 in four unrelated male individuals, consistent with an X-linked recessive mode of ASD, and additionally identify a de novo missense variant in RAB27A (T41A) in an independent ASD family that affects a domain mediating interactions with downstream effectors.

At the molecular level, ASD-associated SYTL4 and RAB27A variants interfere with the interaction between SYTL4 and RAB27A, providing a mechanistic link between human genetic variation and synaptic dysfunction.

Together, these findings implicate disrupted SYTL4-RAB27A-dependent vesicle trafficking in ASD pathogenesis and identify SYTL4 and RAB27A as previously unrecognized contributors to autism-associated synaptic deficits and behavior.

Basic summary

Proc Natl Acad Sci U S A. 2026 Aug 4;123(31):e2605483123. doi: 10.1073/pnas.2605483123. Epub 2026 Jul 30.

ABSTRACT

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired social communication and repetitive behaviors, with genetic studies implicating widespread synaptic dysfunction. However, the contribution of presynaptic vesicle trafficking mechanisms to ASD pathogenesis remains incompletely understood. Here, we identify synaptotagmin-like protein 4 (SYTL4), a RAB27A effector previously characterized in secretory cells, as a regulator of presynaptic function in the mammalian brain. We report a recurrent hemizygous missense variant, R126H, located within the Rab-binding domain of SYTL4 in four unrelated male individuals, consistent with an X-linked recessive mode of ASD, and additionally identify a de novo missense variant in RAB27A (T41A) in an independent ASD family that affects a domain mediating interactions with downstream effectors. Using a R126H knock-in mouse model, we show that R126H knock-in male mice exhibit ASD-relevant behavioral abnormalities accompanied by synaptic deficits in the medial prefrontal cortex. At the molecular level, ASD-associated SYTL4 and RAB27A variants interfere with the interaction between SYTL4 and RAB27A, providing a mechanistic link between human genetic variation and synaptic dysfunction. Together, these findings implicate disrupted SYTL4-RAB27A-dependent vesicle trafficking in ASD pathogenesis and identify SYTL4 and RAB27A as previously unrecognized contributors to autism-associated synaptic deficits and behavior.

PMID:42531028 | DOI:10.1073/pnas.2605483123

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