BLMH and Alzheimer disease

The association between BLMH (HGNC:1059) and Alzheimer disease (MONDO_0004975) has been evaluated in multiple genetic studies and functional assessments. Two independent multi‑patient studies examined BLMH among several candidate genes for Alzheimer disease. In one case‑control study involving 82 Alzheimer disease probands (PMID:11099722), BLMH was included in the panel of genes; however, the study concluded that only the ApoE‑4 allele was an independent risk factor, while the other genes, including BLMH, did not show a significant association. A subsequent meta‑analysis (PMID:17854420) of various genes involved in the beta‑amyloid pathway further suggested that the impact of these polymorphisms on Alzheimer disease risk was rather limited, providing no strong evidence that BLMH contributes substantially to disease susceptibility.

In the realm of genetic evidence, no clearly pathogenic variants or segregation data have been reported that directly implicate BLMH in Alzheimer disease. The absence of a validated coding variant or significant familial clustering translates to a low level of genetic evidence supporting a disease association. Specifically, no HGVS‑formatted variants have been confirmed for BLMH in these studies.

Functional studies have investigated the molecular role of BLMH in cellular processes. One study focused on 14‑3‑3 (Bmh) proteins demonstrated that residues outside the canonical binding motif are crucial for transcriptional regulation (PMID:24142105). Although these assays underscore important biochemical interactions, the direct relevance of such findings to Alzheimer pathogenesis remains unestablished. Moreover, additional functional work on BLMH in other conditions (e.g., atopic eczema) does not provide supportive evidence for an Alzheimer disease mechanism.

Overall, despite inclusion in candidate gene panels and functional insights into protein interactions, both genetic and experimental data have not substantiated a robust association between BLMH and Alzheimer disease. The current evidence therefore falls into the ClinGen category of limited association, reflecting the lack of consistent pathogenic variants, segregation data, and conclusive functional links.

Key take‑home: While BLMH may participate in important cellular processes, its role as a genetic risk factor for Alzheimer disease remains limited and does not support routine clinical diagnostic use at this time.

References

• Journal of the neurological sciences • 2000 • Genetic risk factors of sporadic Alzheimer's disease among Chinese in Taiwan PMID:11099722
• Acta neurologica Scandinavica • 2008 • Meta-analysis of genetic variability in the beta-amyloid production, aggregation and degradation metabolic pathways and the risk of Alzheimer's disease PMID:17854420
• Eukaryotic cell • 2014 • Binding and transcriptional regulation by 14-3-3 (Bmh) proteins requires residues outside of the canonical motif PMID:24142105

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