Genetic alterations in SUPT6H are associated with neurodevelopmental disorders

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Genetic variants in RNA polymerase II complex components are implicated in neurodevelopmental disorders (NDDs).
• SUPT6H, a key transcriptional regulator and histone chaperone, has an uncharacterized role in human NDDs.
• Its essential function in development is highlighted by embryonic lethality in null mice.

Purpose of the Study:

• To investigate the contribution of SUPT6H variants to human NDDs.
• To explore the in vivo consequences of SUPT6H loss-of-function.
• To elucidate the role of SUPT6H in neural development and circuit integrity.

Main Methods:

• Analysis of 18 published SUPT6H single-nucleotide variants (SNVs) using molecular modeling.
• Generation and analysis of conditional Supt6 knockout (KO) mice targeting parvalbumin-expressing interneurons (cKO^PV).
• Assessment of motor function, behavior, and parvalbumin-expressing neuron counts in KO mice.

Main Results:

• Molecular modeling indicated deleterious loss-of-function effects for analyzed SUPT6H variants.
• Homozygous and heterozygous Supt6 KO mice exhibited embryonic lethality, confirming its essential developmental role.
• Postnatal Supt6 deficiency in cKO^PV mice led to motor defects, seizures, and reduced parvalbumin-expressing interneurons, with heterozygous mice showing relevant behavioral phenotypes.

Conclusions:

• Deleterious SUPT6H variants are strongly associated with the etiology of NDDs.
• SUPT6H is critical for maintaining interneuron populations and neural circuit integrity.
• SUPT6H dysfunction offers potential therapeutic targets for NDDs.