Loss of function variants in TMPRSS7 linked to a neurodevelopmental disorder disrupt synaptic function

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Over half of neurodevelopmental disorders lack a known molecular cause.
• Central nervous system (CNS) malformations are recurrent in some families.
• TMPRSS7 encodes matriptase-3, a protease involved in extracellular signaling.

Purpose of the Study:

• To identify the genetic cause of a neurodevelopmental disorder in a Chinese family with recurrent CNS malformations.
• To investigate the function of TMPRSS7 in neurodevelopment.
• To explore the molecular mechanisms underlying TMPRSS7-associated neurodevelopmental deficits.

Main Methods:

• Genetic analysis of a family with neurodevelopmental disorder.
• Functional characterization of TMPRSS7 variants in patients.
• Generation and analysis of Tmprss7 knockout mouse models.
• Neurobehavioral testing in knockout mice.
• Multi-omics analysis of brain tissue.

Main Results:

• Compound heterozygous variants in TMPRSS7 (p.R479H and p.S685Kfs*26) were identified in the affected fetus.
• Patients exhibited impaired matriptase-3 zymogen synthesis and defective protease shedding.
• Tmprss7 knockout mice showed dysregulated synaptic structure and function in the brain.
• Knockout mice displayed significant neurobehavioral deficits, including impaired spatial learning and social interaction.
• Multi-omics data revealed disrupted synaptic signaling pathways in the knockout mice's brains.

Conclusions:

• TMPRSS7 is a candidate gene essential for normal neurodevelopment.
• Defects in TMPRSS7 are linked to neurodevelopmental disorders with CNS malformations.
• Matriptase-3 plays a critical role in synaptic development and function.