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Biallelic variants in the patatin-like phospholipase domain–containing protein 6 (PNPLA6) gene underlie an autosomal recessive spectrum of neurodevelopmental and neurodegenerative disorders, including Laurence-Moon syndrome (LM). LM is characterized by progressive spinocerebellar ataxia, spastic paraplegia, hypogonadotropic hypogonadism and chorioretinal dystrophy without trichomegaly.
Initial whole-exome sequencing in six consanguineous families identified eight distinct PNPLA6 mutations in patients with overlapping Oliver-McFarlane and LM phenotypes, confirming autosomal recessive inheritance (8 probands ([PMID:25480986])) with segregation in all families. A subsequent targeted screening of 292 individuals with ataxia or spastic paraplegia revealed eight additional patients harboring biallelic PNPLA6 variants, expanding the cohort to 16 probands across two independent studies ([PMID:25480986]; [PMID:35069422]).
The variant spectrum includes missense substitutions (e.g., c.2149G>A (p.Gly717Ser)), in‐frame duplications, and frameshifts, with recurrent alleles such as c.3355G>A (p.Gly1119Arg) observed in multiple families. All pathogenic changes cluster within the phospholipase catalytic domain or regulatory cNMP-binding regions, consistent with loss-of-function.
Functional assays demonstrate key mechanistic concordance: patient-derived fibroblasts show markedly reduced NTE enzymatic activity and PNPLA6 expression in eye, pituitary, and cerebellum during human development ([PMID:25480986]). In zebrafish pnpla6 morphants, only wild-type human PNPLA6 mRNA—but not mutant mRNAs—rescues locomotor and developmental defects ([PMID:25480986]). Drosophila sws¹ null mutants are rescued by wild-type PNPLA6 but not by disease-associated alleles, indicating partial retention of non‐enzymatic functions by mutants ([PMID:31780887]).
A high-throughput NTE activity assay applied to 23 new and 95 previously reported individuals reclassified 36 variants as pathogenic and established an inverse genotype:activity:phenotype relationship, where a defined NTE activity threshold predicts retinopathy and endocrinopathy; this was recapitulated in an allelic mouse series ([PMID:37333224]; [PMID:38735647]). Collectively, these data support a loss-of-function mechanism with haploinsufficiency in tissues sensitive to phospholipid dysregulation.
Genetic and experimental evidence across six families and eight novel cases over a decade, coupled with multi-model functional validation, yields a Definitive gene–disease association. The autosomal recessive inheritance, clear genotype–phenotype correlations, and robust NTE assay support both diagnostic sequencing and the development of NTE activity as a prognostic biomarker.
Key Take-home: PNPLA6 sequencing is essential for LM diagnosis and informs prognosis via NTE activity threshold measurements.
Gene–Disease AssociationDefinitiveSix families with eight probands in the initial report and independent replication in eight novel cases, with concordant functional validation in fish, fly, and mouse models Genetic EvidenceStrongBiallelic PNPLA6 variants identified in 16 probands from two cohorts; autosomal recessive inheritance; variant spectrum includes missense and truncating alleles ([PMID:25480986]; [PMID:35069422]) Functional EvidenceStrongZebrafish and Drosophila models demonstrate rescue by wild-type but not mutant PNPLA6; NTE activity assays and mouse allelic series confirm a genotype:activity:phenotype threshold ([PMID:25480986]; [PMID:31780887]; [PMID:37333224]; [PMID:38735647]) |