AGTPBP1 – Pontocerebellar Hypoplasia Type 1

AGTPBP1 encodes a cytosolic carboxypeptidase responsible for deglutamylation of polyglutamylated tubulin, a post-translational modification critical for neuronal maintenance. Loss of AGTPBP1 function in mice and sheep leads to cerebellar atrophy due to Purkinje cell degeneration and a motor neuronopathy reminiscent of human pontocerebellar hypoplasia type 1 (PCH1).

Whole-exome sequencing in two unrelated individuals with early onset cerebellar atrophy, global developmental arrest, progressive muscle weakness, feeding and respiratory difficulties, and severe motor neuronopathy identified compound heterozygous AGTPBP1 variants including a nonsense allele c.2842C>T (p.Arg948Ter) and a splice donor variant c.2186+2T>G (PMID:30976113). Segregation analysis confirmed autosomal recessive inheritance in both families.

All reported alleles are predicted loss-of-function; the spectrum includes nonsense, missense (c.2195A>G (p.Tyr732Cys)), and splice site mutations. No additional affected relatives were described, but parental segregation in each family supports pathogenicity (PMID:30976113).

Animal models have been instrumental in establishing biological concordance: AGTPBP1-null (pcd) mice and CCP1-deficient sheep exhibit cerebellar atrophy and motor neuron loss mirroring human PCH1 (PMID:30976113). Purkinje cell-specific transgenic rescue of wild-type Nna1, but not substrate-binding site mutants, prevented ataxia and cell loss, demonstrating the essential function of the metallocarboxypeptidase domain (PMID:16952463).

Further studies of the pcd5J allele, featuring an Asp775 insertion that destabilizes Nna1 protein, confirm loss-of-function as the disease mechanism (PMID:16465590). Conditional knockout of the carboxypeptidase domain induces ER stress and increased tubulin polyglutamylation in Purkinje cells, providing mechanistic insight into neuronal death (PMID:30225910).

No conflicting reports have been described. Integrating genetic and functional data yields a moderate clinical validity for biallelic AGTPBP1 variants in PCH1. Key take-home: AGTPBP1 should be included in diagnostic panels for early-onset cerebellar atrophy with motor neuronopathy to enable accurate diagnosis and genetic counseling.

References

• European Journal of Human Genetics • 2019 • Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy. PMID:30976113
• Molecular and Cellular Neurosciences • 2006 • The carboxypeptidase-like substrate-binding site in Nna1 is essential for the rescue of the Purkinje cell degeneration (pcd) phenotype. PMID:16952463
• Mammalian Genome • 2006 • The Purkinje cell degeneration 5J mutation is a single amino acid insertion that destabilizes Nna1 protein. PMID:16465590
• Journal of Neurochemistry • 2018 • Deletion of exons encoding carboxypeptidase domain of Nna1 results in Purkinje cell degeneration (pcd) phenotype. PMID:30225910

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