Adult Osteosclerotic Metaphyseal Dysplasia With Progressive Osteonecrosis of the Jaws and Abnormal Bone Resorption Pattern Due to a LRRK1 Splice Site Mutation

Abstract

Osteosclerotic metaphyseal dysplasia (OSMD) is a rare autosomal recessive sclerosing skeletal dysplasia. We report on a 34-year-old patient with sandwich vertebrae, platyspondyly, osteosclerosis of the tubular bones, pathologic fractures, and anemia. In the third decade, he developed osteonecrosis of the jaws, which was progressive in spite of repeated surgical treatment over a period of 11 years. An iliac crest bone biopsy revealed the presence of hypermineralized cartilage remnants, large multinucleated osteoclasts with abnormal morphology, and inadequate bone resorption typical for osteoclast-rich osteopetrosis. After exclusion of mutations in TCIRG1 and CLCN7 we performed trio-based exome sequencing. The novel homozygous splice-site mutation c.261G>A in the gene LRRK1 was found and co-segregated with the phenotype in the family. cDNA sequencing showed nearly complete skipping of exon 3 leading to a frameshift (p.Ala34Profs*33). Osteoclasts differentiated from the patient's peripheral blood monocytes were extremely large. Instead of resorption pits these cells were only capable of superficial erosion. Phosphorylation of L-plastin at position Ser5 was strongly reduced in patient-derived osteoclasts showing a loss of function of the mutated LRRK1 kinase protein. Our analysis indicates a strong overlap of LRRK1-related OSMD with other forms of intermediate osteopetrosis, but an exceptional abnormality of osteoclast resorption. Like in other osteoclast pathologies an increased risk for progressive osteonecrosis of the jaws should be considered in OSMD, an intermediate form of osteopetrosis.

Deciphering the LRRK code: LRRK1 and LRRK2 phosphorylate distinct Rab proteins and are regulated by diverse mechanisms

“…Recent structural work reveals that the C-terminal 28 residues of LRRK2 form an elongated α-helix that extends along the entire kinase domain, interacting with both its C-and N-lobes that likely stabilize the kinase domain and may form binding platforms for other LRRK2 regulators [59]. Several autosomal recessive variants that induce frameshift or truncating mutations impact the equivalent C-terminal residues of LRRK1 and cause OSMD [6][7][8][9]. We have found that one of these mutations, namely E1980A-FS, impacts the C-terminal 66 residues and inactivates LRRK1 (Figure 5D).…”

“…Genetic evidence in humans, points towards LRRK1 regulating bone biology and LRRK2 contributing to Parkinson's disease. Autosomal recessive variants that induce frameshift or truncating mutations within the C-terminal domain of LRRK1, that are likely loss of function, cause a severe metabolic bone disorder termed osteosclerotic metaphyseal dysplasia (OSMD) [6][7][8][9]. This is a unique form of osteopetrosis characterized by severe osteosclerosis localized to the metaphyses of long bones [10].…”

Autosomal recessive osteopetrosis: mechanisms and treatments

“…Extremely rare forms of osteoclast-rich osteopetrosis are caused by defects in the carbonic anhydrase 2 ( CA2 ) ( Sly et al, 1983 ), pleckstrin homology and RUN domain-containing M1 ( PLEKHM1 ) ( Van Wesenbeeck et al, 2007 ), leucine-rich repeat kinase 1 ( LRRK1 ) and melanocyte-inducing transcription factor ( MITF ) genes ( Howaldt et al, 2020 ; Iida et al, 2016 ; Lu et al, 2014 ). The pathogenesis of these forms is poorly characterized due to the small number of identified patients.…”

Deciphering the LRRK code: LRRK1 and LRRK2 phosphorylate distinct Rab proteins and are regulated by diverse mechanisms

“…Recent structural work reveals that the C-terminal 28 residues of LRRK2 form an elongated a-helix that extends along the entire kinase domain, interacting with both its C-and N-lobes that likely stabilize the kinase domain and may form binding platforms for other LRRK2 regulators [59]. Several autosomal recessive variants that induce frameshift or truncating mutations impact the equivalent C-terminal residues of LRRK1 and cause OSMD [6][7][8][9]. We have found that one of these mutations, namely E1980A-FS, impacts the C-terminal 66 residues and inactivates LRRK1 ( Fig 5D).…”

“…Genetic evidence in humans, points towards LRRK1 regulating bone biology and LRRK2 contributing to Parkinson's disease. Autosomal recessive variants that induce frameshift or truncating mutations within the Cterminal domain of LRRK1, that are likely loss of function, cause a severe metabolic bone disorder termed osteosclerotic metaphyseal dysplasia (OSMD) [6][7][8][9]. This is a unique form of osteopetrosis characterized by severe osteosclerosis localized to the metaphyses of long bones [10].…”