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Phosphohydroxylysinuria is an autosomal recessive metabolic disorder characterized by variable neurological involvement and joint hyperlaxity. DNA analysis of a patient with extreme joint hyperlaxity revealed compound heterozygosity for c.718G>A (p.Gly240Arg) and c.1310A>T (p.Glu437Val) in PHYKPL, affecting conserved residues and segregating in trans (PMID:23242558). Recombinant expression in Escherichia coli and HEK293T cells demonstrated that both mutant proteins are largely insoluble and lack phosphohydroxylysine phospholyase activity, establishing a loss-of-function mechanism. Two additional patients described with neurological symptoms broaden the phenotypic spectrum but lack molecular confirmation. Current evidence supports a limited gene–disease association pending identification of further unrelated cases.
Key take-home: Biallelic PHYKPL missense variants causing enzyme deficiency confirm phosphohydroxylysinuria diagnoses and guide metabolic care.
Gene–Disease AssociationLimitedOne compound heterozygous case with functional studies demonstrating loss-of-function Genetic EvidenceLimitedSingle proband with two missense variants supports autosomal recessive inheritance Functional EvidenceModerateIn vitro assays show mutant protein insolubility and absence of enzymatic activity |