Compound Heterozygous Variants in the Phospholipase Gene PNPLA6 Cause Hypopituitarism and Vision Loss

PNPLA6 is a conserved lysophospholipase essential for maintaining nervous system integrity. Biallelic mutations in PNPLA6 have been identified in individuals with a broad spectrum of disorders that can include ataxia, vision loss, and pituitary hormone deficiency. Here, we report the identification of novel compound heterozygous variants in PNPLA6 (p.T1115P and p.Pro1142_Ala1143ins14) in a 10‐year‐old girl with combined pituitary hormone deficiency, including growth hormone, thyroid‐stimulating hormone, and gonadotropins. She also has vision loss and neurodevelopmental delay. Functional validation demonstrates that both variants, a missense substitution affecting a highly conserved residue within the catalytic domain and an intronic variant generating a novel splice acceptor site, completely abolish NTE activity, establishing their pathogenicity. Little is known about the cause of hypopituitarism in individuals with PNPLA6 deficiency. Here, we report the cell‐type‐specific expression of PNPLA6 in mouse pituitary development and in adult animals. PNPLA6 is expressed broadly in SOX2+ stem cells within the pituitary primordium as early as e10.5, prior to lineage specification, suggesting a role in progenitor maintenance and early differentiation. In neonates and adults, expression predominates in the cells that produce growth hormone and pro‐opiomelanocortin. These findings suggest that PNPLA6 could influence pituitary development at early stages, as well as contribute to the altered function of hormone‐secreting cells.