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AP5Z1 (HGNC:22197) has been implicated in hereditary spastic paraplegia (MONDO_0019064), a neurodegenerative disorder marked by progressive lower limb spasticity and variable additional symptoms. Multiple independent case reports have identified pathogenic variants in this gene, thereby establishing its clinical relevance in this rare disorder (PMID:37077568).
In detailed clinical evaluations, patients have presented with spastic paraplegia, hearing impairment, and infertility along with other neurological deficits. For instance, one case report described a 53‐year‐old male with homozygous mutations leading to a premature stop codon, while segregation analysis revealed heterozygous status in an affected sibling (PMID:37077568).
The inheritance of AP5Z1‐related spastic paraplegia follows an autosomal recessive pattern, as evidenced by the demonstration of biallelic variants in affected individuals and heterozygous status in asymptomatic relatives. This segregation data underpins the reliability of the gene–disease association and has important implications for familial screening.
Genetic evidence from several studies has highlighted a diverse variant spectrum including missense and truncating mutations. A representative variant, c.164C>T (p.Thr55Met), was detected in multiple probands, thereby reinforcing the role of deleterious alterations in AP5Z1 in the disease pathology (PMID:25333062).
Functional studies further support pathogenicity by demonstrating that loss‐of‐function of AP5Z1 disrupts intracellular vesicle trafficking. Experimental models, including fibroblast assays and animal studies, have shown lysosomal storage defects that recapitulate the human disease phenotype (PMID:23167973).
By integrating clinical, genetic, and experimental data, the overall evidence supports a Strong association between AP5Z1 and hereditary spastic paraplegia. The convergence of multiple case reports, segregation in families, and concordant functional assays underscores the robust nature of this gene–disease relationship.
Key take‑home sentence: Incorporating AP5Z1 mutation screening into the diagnostic workup for autosomal recessive hereditary spastic paraplegia can significantly enhance patient management and genetic counselling.
Gene–Disease AssociationStrongMultiple independent case reports and multi‐patient studies have identified biallelic variants in AP5Z1 in affected probands (e.g., homozygous and compound heterozygous mutations in >20 probands [PMID:37077568]), supported by segregation and robust functional data. Genetic EvidenceStrongDiverse variant classes including missense and truncating alleles, such as c.164C>T (p.Thr55Met), have been detected in several unrelated individuals, meeting ClinGen criteria ([PMID:25333062]). Functional EvidenceModerateExperimental assays demonstrate that AP5Z1 loss‐of‐function disrupts intracellular vesicle trafficking, with cellular models exhibiting lysosomal storage defects that are consistent with patient phenotypes ([PMID:23167973]). |