Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Autosomal recessive mutations in FBXO7 (PARK15) were first linked to a parkinsonian-pyramidal syndrome but have since been identified in patients with typical early-onset and juvenile-onset Parkinson disease (PD), often with levodopa responsiveness and nonmotor features such as depression and anxiety. FBXO7 encodes an F-box substrate adaptor of the SCF E3 ubiquitin ligase complex that regulates proteasomal degradation, mitochondrial quality control, and mitophagy. Loss-of-function FBXO7 alleles impair these pathways and lead to dopaminergic neuron degeneration in multiple model systems.
FBXO7-related PD follows an autosomal recessive inheritance and has been observed in at least 7 unrelated probands with biallelic variants. Two Turkish sibs homozygous for c.101T>G (p.Leu34Arg) presented with typical levodopa-responsive PD and rapid eye movement sleep behavior disorder, depression, and anxiety ([PMID:26010069]). A homozygous truncating variant c.1492C>T (p.Arg498Ter) was identified in a Turkish patient with early-onset PD ([PMID:26882974]). A de novo compound heterozygous pair c.80G>A (p.Arg27His) and c.1162C>T (p.Gln388Ter) was observed in a 28-year-old with impulse control disorder features ([PMID:32894901]). Two brothers with compound heterozygous FBXO7 variants manifested typical early-onset PD without pyramidal signs ([PMID:36274328]), and a pediatric patient carrying the homozygous missense c.749T>C (p.Leu250Pro) exhibited proteasomal and mitochondrial dysfunction ([PMID:38708447]). Segregation data support co-segregation of biallelic FBXO7 variants with disease across multiple families.
Reported pathogenic alleles include missense (e.g., c.101T>G (p.Leu34Arg)), nonsense (c.1492C>T (p.Arg498Ter)), frameshift, and splice-site changes. All probands carry rare, predicted loss-of-function or destabilizing missense variants absent or extremely rare in public controls. No common founder allele has been established.
FBXO7 loss-of-function leads to impaired interaction with the proteasome regulator PI31, decreased proteasome activity, accumulation of poly-ubiquitinated proteins, and defective mitochondrial mitophagy in patient cells and animal models ([PMID:38708447]). PD-linked FBXO7 mutants fail to rescue dopaminergic neuron loss in Drosophila and disrupt SCF-mediated ubiquitination of mitophagy substrates ([PMID:37535686]). Overexpression of mutant FBXO7 aggravates mitochondrial aggregation and ROS generation, while wild-type FBXO7 facilitates Parkin recruitment to damaged mitochondria and promotes neuronal survival ([PMID:27090516]; [PMID:26310625]).
The accumulated genetic and experimental data meet ClinGen Strong clinical validity criteria: at least 7 probands with biallelic FBXO7 variants, segregation in multiple families, and concordant functional assays demonstrating loss of SCF E3 ligase activity and mitophagy dysfunction. Genetic evidence is graded Strong (biallelic variants in AR PD, segregation, variant spectrum), and functional evidence is Moderate (robust in vitro and in vivo models). FBXO7 should be included in diagnostic gene panels for early-onset and juvenile PD, guiding genetic counseling, carrier testing, and potential therapeutic targeting of proteasomal and mitochondrial pathways.
Key Take-home: FBXO7 biallelic loss-of-function variants cause autosomal recessive Parkinson disease through impaired proteasome and mitophagy, supporting its inclusion in clinical genetic testing for PD.
Gene–Disease AssociationStrongSeven unrelated AR PD probands, segregation in Turkish and Yemeni families, concordant functional data Genetic EvidenceStrongBiallelic FBXO7 variants in ≥7 probands across multiple families, segregation, diverse LOF allele classes Functional EvidenceModeratePatient cell assays and in vivo models show impaired proteasome activity and mitophagy; rescue only by WT FBXO7 |