NAA60 – Primary Familial Brain Calcification

This summary reviews the evidence implicating NAA60 as a novel causative gene for primary familial brain calcification (PFBC). PFBC is a monogenic neurodegenerative disorder that manifests with bilateral brain calcifications, movement disorders, and cognitive decline. The association is supported by case‐based reports and multi‐patient studies demonstrating autosomal recessive inheritance and loss-of-function mechanisms.

In a consanguineous Chinese family, a homozygous variant, c.460_461del (p.Asp154LfsTer113) (PMID:39229657), was identified and shown to co-segregate with PFBC in three siblings. This finding provides compelling genetic segregation data where the variant was associated with the disease phenotype in all affected family members.

Multi-patient investigations further expand on this observation by reporting biallelic NAA60 variants in ten individuals from seven unrelated families (PMID:38480682). These studies underscored that a spectrum of loss-of-function alleles, including the recurrent c.460_461del (p.Asp154LfsTer113), contributes to the PFBC phenotype in an autosomal recessive pattern.

The genetic evidence is reinforced by the fact that each identified variant disrupts normal NAA60 function. Detailed mutation analyses indicate that these variants lead to truncated proteins and a resultant loss of functional activity, which is critical for normal N-terminal acetylation. Insertion of inline citations after key numerical data (PMID:39229657; PMID:38480682) further validates this genetic association.

Functional assessment studies have provided strong experimental support by demonstrating that mutant NAA60 proteins exhibit abnormal subcellular localization, particularly a failure to properly target the Golgi, and increased degradation. Complementary cell-based assays and animal models showed that loss of NAA60 results in a deficiency of N-terminal acetylation, which in turn affects the activity and surface expression of key phosphate homeostasis proteins such as SLC20A2 (PMID:39229657; PMID:38480682).

No significant conflicting evidence has been reported, and the integration of genetic data with reproducible functional findings provides a clear mechanistic link between NAA60 deficiency and PFBC pathogenesis. Although additional evidence continues to accumulate, the current body of data comfortably meets ClinGen criteria for a strong gene-disease association.

Key take‑home sentence: The robust genetic and functional evidence supports the clinical utility of NAA60 testing in the diagnostic evaluation of PFBC in an autosomal recessive setting.

References

• Movement disorders : official journal of the Movement Disorder Society • 2024 • A Homozygous Variant in NAA60 Is Associated with Primary Familial Brain Calcification PMID:39229657
• Nature Communications • 2024 • Biallelic NAA60 variants with impaired n-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications PMID:38480682

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