Homozygous deletion of <scp>RAG1</scp>, <scp>RAG2</scp> and 5′ region <scp>TRAF6</scp> causes severe immune suppression and atypical osteopetrosis

Hubshman, Monika Weisz; Basel‐Vanagaite, Lina; Krauss, Aviva C.; Konen, Osnat; Levy, Yair; Garty, Ben‐Zion; Smirin‐Yosef, Pola; Maya, Idit; Lagovsky, Irina; Taub, Ellen; Marom, Daphna; Gaash, Dafna; Shichrur, Keren; Avigad, Smadar; Hayman-Manzur, L.; Villa, Anna; Sobacchi, Cristina; Shohat, Mordechai; Yaniv, Isaac; Stein, Joseph Allen

doi:10.1111/cge.12916

Cited by 10 publications

(4 citation statements)

References 19 publications

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“…Severe combined immunodeficiency (SCID) is caused by a large deletion on chromosome 11 spanning the RAG1 and RAG2 genes and the 5′-region of TRAF6 (Weisz Hubshman et al, 2017).…”

Section: Molecular Pathogenesis Of Different Forms Of Osteopetrosismentioning

confidence: 99%

“…It is likely that these regions are regulatory; in fact, at the protein level, their deletion completely abolishes TRAF6 production. This mutation has been described in a single family, and the osteopetrosis was not generalized, but was pronounced in the pelvis and legs; because both patients, brother and sister, died at a very young age due to a severe immunological defect, it is currently difficult to predict the evolution of the disease in this particular case (Weisz Hubshman et al, 2017).…”

Section: Molecular Pathogenesis Of Different Forms Of Osteopetrosismentioning

confidence: 99%

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Clinical, genetic aspects and molecular pathogenesis of osteopetrosis

Надыршина

Хусаинова

2023

Vestn. VOGiS

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Osteopetrosis (“marble bone”, ICD-10-78.2) includes a group of hereditary bone disorders distinguished by clinical variability and genetic heterogeneity. The name “osteopetrosis” comes from the Greek language: ‘osteo’ means ‘bone’ and ‘petrosis’ means ‘stone’, which characterizes the main feature of the disease: increased bone density caused by imbalances in bone formation and remodeling, leading to structural changes in bone tissue, predisposition to fractures, skeletal deformities. These defects, in turn, affect other important organs and tissues, especially bone marrow and the nervous system. The disease can be autosomal recessive, autosomal dominant, X-linked or sporadic. Autosomal dominant osteopetrosis has an incidence of 1 in 20,000 newborns and autosomal recessive one has 1 in 250,000. To date, 23 genes have been described, structural changes in which lead to the development of osteopetrosis. Clinical symptoms in osteopetrosis vary greatly in their presentation and severity. The mildest skeletal abnormalities are observed in adulthood and occur in the autosomal dominant form of osteopetrosis. Severe forms, being autosomal recessive and manifesting in early childhood, are characterized by fractures, mental retardation, skin lesions, immune system disorders, renal tubular acidosis. Clinical examination and review of radiographs, bone biopsy and genetic testing provide the bases for clinical diagnosis. The early and accurate detection and treatment of the disease are important to prevent hematologic abnormalities and disease progression to irreversible neurologic consequences. Most patients die within the first decade due to secondary infections, bone marrow suppression and/or bleeding. This article summarizes the current state of the art in this field, including clinical and genetic aspects, and the molecular pathogenesis of the osteopetrosis.

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“…Severe combined immunodeficiency (SCID) is caused by a large deletion on chromosome 11 spanning the RAG1 and RAG2 genes and the 5′-region of TRAF6 (Weisz Hubshman et al, 2017).…”

Section: Molecular Pathogenesis Of Different Forms Of Osteopetrosismentioning

confidence: 99%

Section: Molecular Pathogenesis Of Different Forms Of Osteopetrosismentioning

confidence: 99%

Clinical, genetic aspects and molecular pathogenesis of osteopetrosis

Надыршина

Хусаинова

2023

Vestn. VOGiS

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“…Atypical cases of osteopetrosis have been reported in two siblings affected by severe combined immunodeficiency (SCID), who carry a mutation in the TNF receptor-associated factor 6 ( TRAF6 ) gene, the most important adaptor for the RANK/RANKL signaling pathway ( Weisz Hubshman et al, 2017 ). In addition, a heterozygous truncating mutation in the colony-stimulating factor 1 receptor ( CSF1R ) gene, which encodes the macrophage colony-stimulating factor 1 receptor (M-CSF), was reported in the consanguineous parents of two deceased siblings showing osteopetrosis and brain malformations ( Monies et al, 2017 ).…”

Section: Pathogenesis Of Aromentioning

confidence: 99%

Autosomal recessive osteopetrosis: mechanisms and treatments

Penna

Villa

Capo

2021

Disease Models &Amp; Mechanisms

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Autosomal recessive osteopetrosis (ARO) is a severe inherited bone disease characterized by defective osteoclast resorption or differentiation. Clinical manifestations include dense and brittle bones, anemia and progressive nerve compression, which hamper the quality of patients' lives and cause death in the first 10 years of age. This Review describes the pathogenesis of ARO and highlights the strengths and weaknesses of the current standard of care, namely hematopoietic stem cell transplantation (HSCT). Despite an improvement in the overall survival and outcomes of HSCT, transplant-related morbidity and the pre-existence of neurological symptoms significantly limit the success of HSCT, while the availability of human leukocyte antigen (HLA)-matched donors still remains an open issue. Novel therapeutic approaches are needed for ARO patients, especially for those that cannot benefit from HSCT. Here, we review preclinical and proof-of-concept studies, such as gene therapy, systematic administration of deficient protein, in utero HSCT and gene editing.

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“…A recent report described two affected siblings presenting osteopetrosis associated with severe combined immunodeficiency (SCID) caused by a large deletion on chromosome 11 encompassing RAG1 and RAG2 genes and the 5′ region of TRAF6 (TNF receptor-associated factor 6 gene), the most important adaptor for the RANK/RANKL signaling pathway (57).…”

Section: Autosomal Recessive Osteopetrosis (Aro)mentioning

confidence: 99%

One Disease, Many Genes: Implications for the Treatment of Osteopetroses

et al. 2019

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Osteopetrosis is a condition characterized by increased bone mass due to defects in osteoclast function or formation. In the last decades, the molecular dissection of osteopetrosis has unveiled a plethora of molecular players responsible for different forms of the disease, some of which present also primary neurodegeneration that severely limits the therapy. Hematopoietic stem cell transplantation can cure the majority of them when performed in the first months of life, highlighting the relevance of an early molecular diagnosis. However, clinical management of these patients is constrained by the severity of the disease and lack of a bone marrow niche that may delay immune reconstitution. Based on osteopetrosis genetic heterogeneity and disease severity, personalized therapies are required for patients that are not candidate to bone marrow transplantation. This review briefly describes the genetics of osteopetrosis, its clinical heterogeneity, current therapy and innovative approaches undergoing preclinical evaluation.

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Homozygous deletion of RAG1, RAG2 and 5′ region TRAF6 causes severe immune suppression and atypical osteopetrosis

Cited by 10 publications

References 19 publications

Clinical, genetic aspects and molecular pathogenesis of osteopetrosis

Clinical, genetic aspects and molecular pathogenesis of osteopetrosis

Autosomal recessive osteopetrosis: mechanisms and treatments

One Disease, Many Genes: Implications for the Treatment of Osteopetroses

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