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Progressive skeletal defects caused by Kindlin3 deficiency, a model of autosomal recessive osteopetrosis in humans.

ABSTRACT: The cellular and molecular mechanisms of bone development and homeostasis are clinically important, but not fully understood. Mutations in integrins and Kindlin3 in humans known as Leukocyte adhesion deficiencies (LAD) cause a wide spectrum of complications, including osteopetrosis. Yet, the rarity, frequent misdiagnosis, and lethality of LAD preclude mechanistic analysis of skeletal abnormalities in these patients. Here, using inducible and constitutive tissue-specific Kindlin3 knockout (K3KO) mice, we show that the constitutive lack of embryonic-Kindlin3 in myeloid lineage cells causes growth retardation, edentulism, and skull deformity indicative of hydrocephaly. Micro-CT analysis revealed craniosynostosis, choanal stenosis, and micrognathia along with other skeletal abnormalities characteristic of osteopetrosis. A marked progression of osteosclerosis occurs in mature to middle-aged adults, resulting in the narrowing of cranial nerve foramina and bone marrow cavities of long bones. However, postnatal-Kindlin3 is less critical for bone remodeling and architecture. Thus, myeloid Kindlin3 is essential for skeletal development and its deficiency leads to autosomal recessive osteopetrosis (ARO). The study will aid in the diagnosis, management, and treatment choices for patients with LAD-III and ARO.

SUBMITTER: Dudiki T

PROVIDER: S-EPMC9133165 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Progressive skeletal defects caused by Kindlin3 deficiency, a model of autosomal recessive osteopetrosis in humans.

Dudiki Tejasvi T Nascimento Daniel W DW Childs Lauren S LS Kareti Swetha S Androjna Charlie C Zhevlakova Irina I Byzova Tatiana V TV

Bone 20220325

The cellular and molecular mechanisms of bone development and homeostasis are clinically important, but not fully understood. Mutations in integrins and Kindlin3 in humans known as Leukocyte adhesion deficiencies (LAD) cause a wide spectrum of complications, including osteopetrosis. Yet, the rarity, frequent misdiagnosis, and lethality of LAD preclude mechanistic analysis of skeletal abnormalities in these patients. Here, using inducible and constitutive tissue-specific Kindlin3 knockout (K3KO) ...[more]

PMID: 35342016

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Project description:Introduction and importance Autosomal recessive osteopetrosis (ARO) is a group of disease characterized by osteoclast dysfunction inhibiting bone resorption and bone turnover, with TCIRG1-associated ARO leading to autosomal recessive infantile malignant osteopetrosis (OPTB1, MIM entry number # 259700). While most patients with TCIRG1-associated osteopetrosis present a malignant clinical course and shortened lifespan, a few cases of mild osteopetrosis associated with TCIRG1 have been reported recently. In this study we report a rare case of non-malignant TCIRG1-associated osteopetrosis, with detail clinical characterization, genetic analysis and underwent successful total hip replacement surgery. Case presentation 24-year-old female patient came to us with limp gait, hip pain in both sides, severe stiffness. She suffered multiple fractures, bilateral hip osteoarthritis, right leg was 2 cm shorter compared with left leg. The patient had a limp gait due to severe pain and leg length discrepancy. Clinical discussion Whole Exome Sequencing, result of genetic analysis shown the patient had a compound heterozygous genotype at TCIRG1 (c.1194dup, p.Gly399ArgTer and c.334G > A, p.Gly112Arg). Total hip replacement was performed. The joint exposure and femoral canal reaming was difficult due to complete deformity of femoral head, loss of canal and high bone density. Post-operation period was uneventful; the patient rehabilitated as planned without further complication. Conclusion This is the first case of TCIRG1-associated osteopetrosis reported in Vietnam and one of the few cases of non-malignant TCIRG1-associated osteopetrosis. This case report suggests that total hip replacement is a viable option for the treatment of hip osteoarthritis in patients with mild form osteopetrosis. Highlights • This is the first case of TCIRG1-associated osteopetrosis reported in Vietnam with clinical and genetic workup.• This study detailed the surgical processes as well as the rehabilitation period of a patient with mild form of osteopetrosis.• Total hip arthroplasty is a feasible option for the treatment of hip osteoarthritis in osteopetrosis patients• High bone density, brittle/fragile bone, deformed acetabulum, narrow or sealed femoral canal leads to difficulty in surgery.

Dataset Information

Progressive skeletal defects caused by Kindlin3 deficiency, a model of autosomal recessive osteopetrosis in humans.

Publications

Progressive skeletal defects caused by Kindlin3 deficiency, a model of autosomal recessive osteopetrosis in humans.

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