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PEX16 encodes a 336-amino-acid peroxisomal membrane protein essential for early peroxisome membrane biogenesis. Peroxisome biogenesis disorders, including Zellweger syndrome, are severe autosomal recessive conditions characterized by hypotonia and neuronal migration defects. Genetic heterogeneity in this disease class spans at least eleven PEX genes, with PEX16 assigned to complementation group D based on functional complementation assays (PMID:11405337).
Initial reports identified a homozygous nonsense variant c.526C>T (p.Arg176Ter) in a patient with classical Zellweger syndrome. Subsequent analysis in two unrelated patients (D-02, D-03) uncovered a homozygous splice-site mutation c.112+2T>G causing exon 10 skipping and introducing a premature stop at codon 336. All three probands lacked peroxisomal membrane ghosts in fibroblasts, confirming loss of Pex16p function (PMID:11890679).
The variant spectrum in PEX16 includes multiple loss-of-function alleles: nonsense (e.g., p.Arg176Ter), frameshift (e.g., c.146del (p.Leu49fs)), and splice-site mutations (e.g., c.112+2T>G). These alleles occur in homozygous or compound heterozygous states under an autosomal recessive inheritance model, with carrier frequencies undetermined. No recurrent or founder variants have been established to date.
Functional studies demonstrate that patient fibroblasts homozygous for PEX16 mutations completely lack peroxisomal membranes, consistent with a loss-of-function (haploinsufficiency) mechanism. Restoration of Pex16p in cellular models rescues peroxisome assembly, corroborating the pathogenicity of these variants.
Broad genetic surveys of peroxisome biogenesis disorders include PEX16 among ten other PEX genes implicated in early peroxisome formation. Although knockout mouse models are forthcoming, current human cellular data provide a direct link between PEX16 disruption and clinical phenotype.
Integration of genetic and experimental findings supports a Strong clinical validity classification for PEX16 in peroxisome biogenesis disorders, with Strong genetic evidence and Moderate functional evidence. Key take-home: PEX16 genotyping should be incorporated into diagnostic panels for Zellweger spectrum disorders to guide early clinical management.
Gene–Disease AssociationStrongThree unrelated probands and concordant cellular functional data demonstrating disrupted peroxisome membrane biogenesis (PMID:11890679) Genetic EvidenceStrongThree loss-of-function variants in three unrelated autosomal recessive probands, reaching the ClinGen genetic evidence cap Functional EvidenceModeratePatient fibroblast assays show complete absence of peroxisomal membranes consistent with loss-of-function mechanism |