LRRK1 and Osteosclerotic Metaphyseal Dysplasia

LRRK1 has emerged as a key gene underlying osteosclerotic metaphyseal dysplasia (OSMD), a rare skeletal dysplasia characterized by severe osteosclerosis at the metaphyses, recurrent fractures, and other skeletal anomalies. Multiple independent studies have identified biallelic loss‑of‑function mutations in LRRK1 in affected individuals, and the robust autosomal recessive inheritance pattern has been consistently demonstrated (PMID:27055475).

Genetic evidence spans several case reports and multi‑patient studies where distinct families harbor frameshift, splice‑site, and stop gain mutations. For example, the mutation c.5939_5945del (p.Glu1980fs) was identified in a patient whose phenotype closely recapitulated that seen in Lrrk1‑deficient mouse models. Familial segregation analysis, especially in consanguineous families, further reinforces the causality of these variants (PMID:27829680).

The variant spectrum for LRRK1 in OSMD is diverse yet consistently pathogenic. In addition to the aforementioned frameshift deletion, other recurrent alterations have been reported across different populations. These findings consolidate the genetic basis of OSMD and underscore the clinical relevance of evaluating LRRK1 mutations in patients presenting with the characteristic radiographic and skeletal findings (PMID:31571209).

Segregation data across multiple families confirm an autosomal recessive mode of inheritance, with affected siblings and additional relatives exhibiting consistent phenotypes. This data, alongside detailed mutation analyses, supports a strong gene–disease association and aids in the diagnostic evaluation of suspected OSMD patients (PMID:32119750).

Functional studies provide additional support, as assays using patient‑derived osteoclasts and Lrrk1 knockout models showed impaired bone resorption and disrupted RAC1/Cdc42 signaling. These experiments mirror the clinical manifestations and reinforce a loss‑of‑function mechanism as the pathogenic basis for OSMD (PMID:27600824).

In summary, the convergence of robust genetic data and concordant functional studies establishes a strong association between LRRK1 mutations and osteosclerotic metaphyseal dysplasia. This evidence not only enhances diagnostic accuracy but also supports potential clinical interventions tailored to the underlying mechanism. Key take‑home message: LRRK1 is a critical gene in OSMD, and its mutation spectrum offers valuable insights for diagnostic decision‑making and future therapeutic strategies.

References

• Journal of Medical Genetics • 2016 • Identification of biallelic LRRK1 mutations in osteosclerotic metaphyseal dysplasia and evidence for locus heterogeneity PMID:27055475
• Journal of Human Genetics • 2017 • Identification of a novel LRRK1 mutation in a family with osteosclerotic metaphyseal dysplasia PMID:27829680
• Annals of Human Genetics • 2020 • A novel homozygous LRRK1 stop gain mutation in a patient suspected with osteosclerotic metaphyseal dysplasia PMID:31571209
• Journal of Bone and Mineral Research • 2020 • Adult Osteosclerotic Metaphyseal Dysplasia With Progressive Osteonecrosis of the Jaws and Abnormal Bone Resorption Pattern Due to a LRRK1 Splice Site Mutation PMID:32119750
• American Journal of Physiology. Endocrinology and Metabolism • 2016 • Leucine-rich repeat kinase-1 regulates osteoclast function by modulating RAC1/Cdc42 Small GTPase phosphorylation and activation PMID:27600824

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