PNPLA6

Ciliogenesis screen results (2 screens)

• Wheway et al. 2015 (siRNA) [siRNA]: Ciliogenesis Defect (z=-6.82) PMID:26167766
• Breslow et al. 2018 (CRISPR) [CRISPR]: Increased Signaling (Negative Regulator) PMID:29459680

Phenotypes

Human ciliopathy phenotype:

Laurence-Moon Syndrome (and PNPLA6 spectrum): cerebellar ataxia, visual impairment (chorioretinal dystrophy/retinopathy), anterior hypopituitarism (hypogonadotropic hypogonadism, growth hormone deficiency), hair anomalies (trichomegaly), gait disturbance, spasticity. NTE activity correlates inversely with retinopathy and endocrinopathy severity (Liu 2024).

Ciliopathy associations

• Laurence-Moon Syndrome

References: PMID:38735647, PMID:25480986

Subcellular localization

endoplasmic reticulum

References: PMID:38735647

Functional category

• Metabolism
• Signaling (Hedgehog, GPCRs, ion channels)

Function

PNPLA6 encodes neuropathy target esterase (NTE), a lysophospholipase that hydrolyses lysophosphatidylcholine at the endoplasmic reticulum. Biallelic pathogenic PNPLA6 variants cause a continuous spectrum of disorders defined by an NTE genotype:activity:phenotype relationship (Liu et al. 2024 Brain, PMID 38735647): spastic paraplegia type 39 (SPG39, OMIM #612020), Gordon-Holmes syndrome (cerebellar ataxia + hypogonadotropic hypogonadism, OMIM #212840), Boucher-Neuhauser syndrome (cerebellar ataxia + hypogonadism + chorioretinal dystrophy, OMIM #215470), Laurence-Moon syndrome (OMIM #245800), and Oliver-McFarlane syndrome (OMIM #275400). The Liu 2024 study of 23 new patients plus 95 reported individuals established NTE esterase activity as a robust functional assay (reclassifying 46 variants as pathogenic/likely pathogenic) and revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy — recapitulated in vivo in an allelic mouse series. Phenotypically, the Laurence-Moon spectrum (gait disturbance, visual impairment, anterior hypopituitarism, hair anomalies) overlaps substantially with classic ciliopathies, particularly Bardet-Biedl syndrome. Note: the cilia mechanism is inferred from phenotypic overlap with BBS and from the chorioretinal/hypopituitary/hypothalamic phenotype rather than a direct demonstration of ciliary localization of NTE protein.