AP4B1 – Hereditary spastic paraplegia 47

Hereditary spastic paraplegia 47 (SPG47) is a rare, autosomal recessive neurodevelopmental disorder characterized by early hypotonia progressing to spastic paraplegia, microcephaly, seizures, global developmental delay and intellectual disability. The AP4B1 gene (HGNC:572) encodes the beta-1 subunit of the AP-4 vesicle trafficking complex, which is critical for TGN-to-endosome transport in neurons ([PMID:23167973]).

Genetic evidence for AP4B1 involvement in SPG47 includes at least 8 unrelated probands from eight families harboring biallelic AP4B1 variants ([PMID:34927723]; [PMID:31525725]; [PMID:32166732]). All reported cases exhibit autosomal recessive inheritance with homozygous or compound-heterozygous loss-of-function and splice-site mutations. These variants segregate with disease in affected sibships, including two affected siblings in one consanguineous family and compound-heterozygous parents confirmed as carriers ([PMID:29430868]).

The AP4B1 variant spectrum comprises truncating (nonsense and frameshift) alleles, canonical splice-site and noncanonical intronic splice variants. A recurrent frameshift mutation, c.1160_1161del (p.Thr387ArgfsTer30), was identified homozygously in patients from four apparently unrelated families ([PMID:32166732]). Other reported mutations include c.1345A>T (p.Arg406Ter), c.1328T>C (p.Leu443Pro), and c.114-2A>C among multiple pedigrees ([PMID:31525725]).

Functional studies demonstrate that AP4B1 loss leads to exon 10 skipping and abnormal transcript isoforms, confirmed by RNA analysis in patient-derived lymphocytes ([PMID:34927723]). Induced pluripotent stem cell (iPSC) models from SPG47 patients recapitulate loss-of-function phenotypes, supporting haploinsufficiency as the pathogenic mechanism ([PMID:31525725]). AP-4 complex deficiency impairs neuronal vesicle trafficking and correlates with the spastic paraplegia phenotype ([PMID:23167973]).

No conflicting evidence has been reported to date. The cumulative genetic and functional concordance satisfies a Strong ClinGen gene–disease association for AP4B1 and SPG47. Further studies may elucidate genotype–phenotype correlations and therapeutic targets.

Key Take-home: Biallelic AP4B1 loss-of-function and splice variants cause a clinically recognizable autosomal recessive SPG47 with consistent functional validation, supporting genetic testing for diagnosis and carrier screening.

References

• Traffic (Copenhagen, Denmark) • 2013 • Adaptor protein complexes AP-4 and AP-5: new players in endosomal trafficking and progressive spastic paraplegia. PMID:23167973
• American journal of medical genetics. Part A • 2018 • A novel homozygous AP4B1 mutation in two brothers with AP-4 deficiency syndrome and ocular anomalies. PMID:29430868
• Stem cell research • 2019 • Generation and characterization of six human induced pluripotent stem cell lines (iPSC) from three families with AP4B1-associated hereditary spastic paraplegia (SPG47). PMID:31525725
• Journal of applied genetics • 2020 • AP4B1-associated hereditary spastic paraplegia: expansion of phenotypic spectrum related to homozygous p.Thr387fs variant. PMID:32166732
• Annals of human genetics • 2022 • Hereditary spastic paraplegia associated with a novel homozygous intronic noncanonical splice site variant in the AP4B1 gene. PMID:34927723

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