Broadening the phenotype of LRRK1 mutations - Features of malignant osteopetrosis and optic nerve atrophy with intrafamilial variable expressivity

Chorin, Odelia; Chowers, Guy; Agbariah, Rawan; Karklinsky, Shani; Barel, Ortal; Bar-Joseph, Ifat; Reznik‐Wolf, Haike; Shemesh, Jana; Pode‐Shakked, Ben; Jacobson, Jeffrey M.; Huna‐Baron, Ruth; Redler, Yael; Tirosh, Irit; Vivante, Asaf; Raas‐Rothschild, Annick

doi:10.1016/j.ejmg.2021.104383

Cited by 11 publications

(24 citation statements)

References 14 publications

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“…Patient 4, 11 years old, revealed in our research laboratory no mutation in any of the five genes (SLC29A3, TNFRSF11A, LRRK1, (5,21,31,32) TNFRSF11A (4/4) (11,20,33,34) TCIRG1 (2/1) (21) CSF1R (11/5) (22,35,36) LRRK1 (8/5) (13)(14)(15)(16)(17)…”

Section: Patientmentioning

confidence: 98%

“…Iranian(1), Indian(2), Moroccan(1), Bulgarian (5,21,31,32) TNFRSF11A (4/4) (11,20,33,34) TCIRG1 (2/1) (21) CSF1R (11/5) (22,35,36) LRRK1 (8/5) (13)(14)(15)(16)(17) Metaphyseal sclerosis When referred to us at age 28 months, his height, weight, and head circumference Z-scores were À1.8, À4.2, and À3.0, respectively. Dysmorphic facial features included a wide forehead, triangular face with open mouth, high-arched palate, yellow teeth, short nose with prominent nasal tip, long philtrum, mild hypoplasia of alae nasi, nasal obstruction, rigid pinnae, almondshaped eyes with gray sclera, and laterally anteverted palpebral fissures (Kabuki makeup syndrome-like).…”

Section: Mutationsmentioning

confidence: 99%

“…The eight individuals reported to date with "osteosclerotic metaphyseal dysplasia" (OMIM % 615198) (3) harbored homozygous defects of LRRK1. (13)(14)(15)(16)(17) Their clinical and radiographic features of DSS resemble those attributable to SLC29A3 or TCIRG1 mutation, including fractures without severe extramedullary hematopoiesis or short stature. (13)(14)(15)(16)(17) Radiological features include metaphyseal and vertebral sclerosis with mildly under-modeled long bones that may evolve, including diminishing metaphyseal sclerosis.…”

Section: Lrrk1-associated Osteosclerotic Metaphyseal Dysplasiamentioning

confidence: 99%

“…In 2016, Iida and colleagues (13) associated "leucine rich repeat kinase 1" (LRRK1) with osteosclerotic metaphyseal dysplasia (OMD; OMIM % 615198) (3) featuring characteristics of DSS. (3,(13)(14)(15)(16)(17) In 2018, two genes underlying autosomal recessive OPT (18,19) became associated with DSS (20,21) : (i) "tumor necrosis factor receptor superfamily member 11A" (TNFRSF11A) that encodes receptor activator of NF-κB (RANK) (OMIM # 612301), (3) and (ii) "T-cell immune regulator 1" (TCIRG1) that encodes a component of the vacuolar proton (H+) pump necessary for osteoclasts (OCs) to produce hydrochloric acid (OMIM # 259700). (3) Most recently, in 2019, biallelic mutations of "colony-stimulating factor 1 receptor" (CSF1R) (22) were associated with dysosteosclerosis-Pyle disease (DSS-PD), also called "brain abnormalities, neurodegeneration, and dysosteosclerosis" (BANDDOS: OMIM # 618476).…”

Section: Introductionmentioning

confidence: 99%

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Dysosteosclerosis: Clinical and Radiological Evolution Reflecting Genetic Heterogeneity

et al. 2022

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Dysosteosclerosis (DSS), the term coined in 1968 for ultrarare dysplasia of the skeleton featuring platyspondyly with focal appendicular osteosclerosis, has become generic by encompassing the genetic heterogeneity recently reported for this phenotype. We studied four unrelated Turkish patients with DSS to advance understanding of the new nosology. Patient 1 suffered femur fractures beginning at age 1 year. DSS was suspected from marked metaphyseal osteosclerosis in early childhood and subsequently platyspondyly accompanying patchy osteosclerosis of her appendicular skeleton. She harbored in SLC29A3, in 2012 the first gene associated with DSS, a unique homozygous duplication (c.303_320dup, p.102_107dupYFESYL). Patient 2 presented similarly with fractures and metaphyseal osteosclerosis but with no platyspondyly at age 2 months. She was homozygous for a novel nonsense mutation in SLC29A3 (c.1284C>G, p.Tyr428*). Patient 3 had ocular disease at age 2 years, presented for short stature at age 11 years, and did not begin to fracture until age 16 years. Radiographs showed mild platyspondyly and focal metaphyseal and femoral osteosclerosis. She was homozygous for a unique splice site mutation in TNFRSF11A (c.616+3A>G). Patient 4 at age 2 years manifested developmental delay and frequent infections but did not fracture. He had unique metadiaphyseal splaying and osteosclerosis, vertebral end‐plate osteosclerosis, and cortical thinning of long bones but no mutation was detected of SLC29A3, TNFRSF11A, TCIRG1, LRRK1, or CSF1R associated with DSS. We find that DSS from defective SLC29A3 presents earliest and with fractures. DSS from compromised TNFRSF11A can lead to optic atrophy as an early finding. Negative mutation analysis in patient 4 suggests further genetic heterogeneity underlying the skeletal phenotype of DSS. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Section: Patientmentioning

confidence: 98%

Section: Mutationsmentioning

confidence: 99%

Section: Lrrk1-associated Osteosclerotic Metaphyseal Dysplasiamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dysosteosclerosis: Clinical and Radiological Evolution Reflecting Genetic Heterogeneity

et al. 2022

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“…46 Loss-of-function variants in this gene have been linked to the rare disorder osteosclerotic metaphyseal dysplasia (MIM: 615198). 47,48 LUM on the other hand codes for an extracellular matrix protein called lumican, a small leucine-rich repeat proteoglycan (SLRP) that regulates the assembly of collagens into higher-order fibrils in connective tissues. Due to deregulated growth of abnormally thick collagen fibrils, mice homozygous for a lumican null mutation develop Ehlers-Danlos syndrome (EDS)-like skin fragility and laxity, and bilateral corneal opacification.…”

Section: Finnish-enriched Protein Coding Risk Variantsmentioning

confidence: 99%

A meta-analysis of genome-wide association studies in 614,243 individuals identifies 59 novel susceptibility loci underlying Dupuytren’s contracture

Rahimov

Degner

Lee

et al. 2022

Preprint

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Dupuytren’s contracture or disease (DD) is a disabling, fibroproliferative disease of the hand that affects up to 25% of people of northwestern European descent. It typically manifests in adulthood and many affected individuals have a positive family history, yet the genetic architecture of DD is not completely understood. We conducted genome-wide association studies (GWAS) of DD in 8,846 cases and 347,659 population controls from the UK Biobank resource, and 4,616 cases and 253,122 population controls from the FinnGen study. We combined these datasets with a meta-analysis, which represents the largest GWAS conducted in DD to date including 13,462 cases. We identified 83 loci with genome-wide significance of p < 5 × 10-8. We replicated association at the 24 previously reported loci and discovered 59 novel loci, substantially increasing the number of risk loci for DD. Colocalization with expression quantitative trait loci and overlap with genes linked to phenotypically matched human Mendelian disorders or animal models support causal roles for at least 30 genes with high confidence. Among these, fifteen genes cause rare limb abnormalities when mutated, an observation that may potentially shed light on hand specificity of DD phenotype. Gene enrichment analysis revealed predominant role of connective tissue development and maintenance and extracellular matrix homeostasis but limited or no role of inflammatory processes in disease causality. These findings provide key insights into the biological mechanisms underlying DD and identify genetically informed therapeutic targets for DD and possibly for other fibrotic diseases.

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Osteosclerotic Metaphyseal Dysplasia Due to a Likely Pathogenic LRRK1 Variant as a Cause of Recurrent Long Bone Fractures

et al. 2023

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Osteosclerotic metaphyseal dysplasia (OSMD) is a very rare autosomal‐recessive disease caused by mutations in the leucine‐rich repeat kinase 1 (LRRK1) gene. It is a sclerosing skeletal dysplasia characterized by osteosclerosis of the long bones, predominantly at the metaphyses and vertebrae. Phenotypic features can be short stature, pathological fractures, delayed development, and hypotonia, but they are not uniformly present, and relatively few cases are known from the literature. A 40‐year‐old man was seen at our bone center because of nonspontaneous multiple peripheral low‐energy trauma fractures since puberty. He had no other complaints and his family history was negative. Except for a relatively short stature (167 cm; −1.5 SD), there were no abnormalities on examination, including laboratory tests. Initially, a suspicion was raised of osteogenesis imperfecta, but bone mineral density was high and X‐rays of the whole skeleton showed osteosclerosis of the metaphyses of long bones and vertebrae. Whole‐exome sequencing showed a homozygous, likely pathogenic, variant (American College of Medical Genetics and Genomics criteria class 4) in the LRRK1 gene, fitting the diagnosis of OSMD. In conclusion, we described a 40‐year‐old patient with osteosclerotic metaphyseal dysplasia caused by a homozygous variant in the LRRK1 gene, resulting in multiple fractures of the long bones without other features of the disease, adding to the phenotypic variation of OSMD. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Broadening the phenotype of LRRK1 mutations - Features of malignant osteopetrosis and optic nerve atrophy with intrafamilial variable expressivity

Cited by 11 publications

References 14 publications

Dysosteosclerosis: Clinical and Radiological Evolution Reflecting Genetic Heterogeneity

Dysosteosclerosis: Clinical and Radiological Evolution Reflecting Genetic Heterogeneity

A meta-analysis of genome-wide association studies in 614,243 individuals identifies 59 novel susceptibility loci underlying Dupuytren’s contracture

Osteosclerotic Metaphyseal Dysplasia Due to a Likely Pathogenic LRRK1 Variant as a Cause of Recurrent Long Bone Fractures

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