TYROBP – Nasu-Hakola Disease

Nasu-Hakola disease, also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, is a rare autosomal recessive disorder characterized by adolescent-onset pathological fractures (HP:0002756, HP:0002757) and progressive presenile dementia (HP:0000726) with basal ganglia calcification (HP:0002135) and bone cysts (HP:0012062). Biallelic mutations in TYROBP (DAP12) disrupt the TREM2–DAP12 signaling complex in osteoclasts and microglia, leading to skeletal and neurological pathology.

Genetic analyses across multiple cohorts identified at least 23 probands with TYROBP biallelic variants (PMID:10888890), including a shared Finnish founder deletion and a Japanese null allele (PMID:12370476), seven cases with frameshift and missense mutations (PMID:27904822), and additional compound heterozygotes with c.82C>T (p.Gln28Ter) and c.141del (p.Met48fs) (PMID:17125796). The variant spectrum comprises nonsense, frameshift, splice-site, and rare missense alleles.

Segregation in families confirms recessive inheritance: an Italian kindred showed concordant variants in an affected sibling (PMID:23399524), and a Finnish sibship harbored a homozygous DAP12 deletion in three affected siblings (PMID:24612676), totaling five additional affected relatives beyond index cases.

Functional assays demonstrate that TYROBP loss-of-function impairs osteoclast differentiation and bone resorption, as human pre-osteoclasts fail to form mature osteoclasts without DAP12 (PMID:16418779) and Tyrobp−/− mice exhibit osteopetrosis (PMID:17966394). Microglial models show deficient activation and phagocytosis in the absence of DAP12, while rescue of TREM2–DAP12 signaling restores function (PMID:31396216).

Heterozygous TYROBP deletion carriers do not exhibit significant cognitive impairment in aging cohorts (PMID:29336840), and no association with multiple sclerosis has been observed (PMID:19019460), indicating that monoallelic variants are insufficient to cause PLOSL.

Collectively, strong genetic and moderate functional evidence support a robust association between biallelic TYROBP variants and Nasu-Hakola disease. Inclusion of TYROBP in diagnostic gene panels is recommended for early-onset dementia with bone lesions, and targeted therapies modulating DAP12 signaling warrant investigation.

References

• Nature genetics • 2000 • Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts. [PMID:10888890]
• Neurology • 2002 • Heterogeneity of presenile dementia with bone cysts (Nasu-Hakola disease): three genetic forms. [PMID:12370476]
• Intractable & rare diseases research • 2016 • Targeted sequencing approach to identify genetic mutations in Nasu-Hakola disease. [PMID:27904822]
• Journal of the neurological sciences • 2013 • Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL): a new report of an Italian woman and review of the literature. [PMID:23399524]
• Bone • 2019 • Bone matrix hypermineralization associated with low bone turnover in a case of Nasu-Hakola disease. [PMID:30316000]
• Journal of the neurological sciences • 2007 • A novel compound heterozygous mutation in the DAP12 gene in a patient with Nasu-Hakola disease. [PMID:17125796]
• Journal of bone and mineral research • 2006 • TREM2, a DAP12-associated receptor, regulates osteoclast differentiation and function. [PMID:16418779]
• Advances in experimental medicine and biology • 2007 • The enigmatic function of TREM-2 in osteoclastogenesis. [PMID:17966394]
• Frontiers in immunology • 2019 • Phenotypic Expansion in Nasu-Hakola Disease: Immunological Findings in Three Patients and Proposal of a Unifying Pathogenic Hypothesis. [PMID:31396216]
• Neurobiology of aging • 2018 • Heterozygous TYROBP deletion (PLOSLFIN) is not a strong risk factor for cognitive impairment. [PMID:29336840]
• Journal of neuroimmunology • 2009 • No evidence for shared etiology in two demyelinative disorders, MS and PLOSL. [PMID:19019460]

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