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1.
PLoS Genet ; 12(7): e1006156, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27441836

RESUMEN

Recessive osteogenesis imperfecta (OI) is caused by defects in proteins involved in post-translational interactions with type I collagen. Recently, a novel form of moderately severe OI caused by null mutations in TMEM38B was identified. TMEM38B encodes the ER membrane monovalent cation channel, TRIC-B, proposed to counterbalance IP3R-mediated Ca2+ release from intracellular stores. The molecular mechanisms by which TMEM38B mutations cause OI are unknown. We identified 3 probands with recessive defects in TMEM38B. TRIC-B protein is undetectable in proband fibroblasts and osteoblasts, although reduced TMEM38B transcripts are present. TRIC-B deficiency causes impaired release of ER luminal Ca2+, associated with deficient store-operated calcium entry, although SERCA and IP3R have normal stability. Notably, steady state ER Ca2+ is unchanged in TRIC-B deficiency, supporting a role for TRIC-B in the kinetics of ER calcium depletion and recovery. The disturbed Ca2+ flux causes ER stress and increased BiP, and dysregulates synthesis of proband type I collagen at multiple steps. Collagen helical lysine hydroxylation is reduced, while telopeptide hydroxylation is increased, despite increased LH1 and decreased Ca2+-dependent FKBP65, respectively. Although PDI levels are maintained, procollagen chain assembly is delayed in proband cells. The resulting misfolded collagen is substantially retained in TRIC-B null cells, consistent with a 50-70% reduction in secreted collagen. Lower-stability forms of collagen that elude proteasomal degradation are not incorporated into extracellular matrix, which contains only normal stability collagen, resulting in matrix insufficiency. These data support a role for TRIC-B in intracellular Ca2+ homeostasis, and demonstrate that absence of TMEM38B causes OI by dysregulation of calcium flux kinetics in the ER, impacting multiple collagen-specific chaperones and modifying enzymes.


Asunto(s)
Calcio/metabolismo , Colágeno Tipo I/biosíntesis , Canales Iónicos/genética , Osteogénesis Imperfecta/genética , Adulto , Señalización del Calcio , Colágeno Tipo I/metabolismo , Consanguinidad , Análisis Mutacional de ADN , Retículo Endoplásmico/metabolismo , Estrés del Retículo Endoplásmico , Femenino , Genes Recesivos , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Homeostasis , Humanos , Lactante , Masculino , Linaje , Procesamiento Proteico-Postraduccional
2.
JBJS Case Connect ; 11(3)2021 07 23.
Artículo en Inglés | MEDLINE | ID: mdl-34297706

RESUMEN

CASE: Cortical atrophy, or stress shielding, secondary to a large-diameter femoral intramedullary rod was noted over almost a decade in a now 14-year-old girl with osteogenesis imperfecta (OI). After an initial minimally invasive unsuccessful revision, we downsized the left femur rod with realignment and noted restoration of the left femur cortical thickness. CONCLUSION: We demonstrate the significant functional impact of stress shielding and its evolution over a protracted period and outline treatment principles. To our knowledge, this is the first report of treatment of stress shielding of a long bone in the setting of OI.


Asunto(s)
Osteogénesis Imperfecta , Adolescente , Femenino , Arteria Femoral , Fémur , Humanos , Fijadores Internos , Extremidad Inferior , Osteogénesis Imperfecta/complicaciones , Osteogénesis Imperfecta/cirugía
3.
J Clin Endocrinol Metab ; 102(6): 2019-2028, 2017 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-28323974

RESUMEN

Context: Recessive mutations in TMEM38B cause type XIV osteogenesis imperfecta (OI) by dysregulating intracellular calcium flux. Objectives: Clinical and bone material phenotype description and osteoblast differentiation studies. Design and Setting: Natural history study in pediatric research centers. Patients: Eight patients with type XIV OI. Main Outcome Measures: Clinical examinations included bone mineral density, radiographs, echocardiography, and muscle biopsy. Bone biopsy samples (n = 3) were analyzed using histomorphometry, quantitative backscattered electron microscopy, and Raman microspectroscopy. Cellular differentiation studies were performed on proband and control osteoblasts and normal murine osteoclasts. Results: Type XIV OI clinical phenotype ranges from asymptomatic to severe. Previously unreported features include vertebral fractures, periosteal cloaking, coxa vara, and extraskeletal features (muscular hypotonia, cardiac abnormalities). Proband lumbar spine bone density z score was reduced [median -3.3 (range -4.77 to +0.1; n = 7)] and increased by +1.7 (1.17 to 3.0; n = 3) following bisphosphonate therapy. TMEM38B mutant bone has reduced trabecular bone volume, osteoblast, and particularly osteoclast numbers, with >80% reduction in bone resorption. Bone matrix mineralization is normal and nanoporosity low. We demonstrate a complex osteoblast differentiation defect with decreased expression of early markers and increased expression of late and mineralization-related markers. Predominance of trimeric intracellular cation channel type B over type A expression in murine osteoclasts supports an intrinsic osteoclast defect underlying low bone turnover. Conclusions: OI type XIV has a bone histology, matrix mineralization, and osteoblast differentiation pattern that is distinct from OI with collagen defects. Probands are responsive to bisphosphonates and some show muscular and cardiovascular features possibly related to intracellular calcium flux abnormalities.


Asunto(s)
Coxa Vara/fisiopatología , Canales Iónicos/genética , Osteoblastos/fisiología , Osteoclastos/fisiología , Osteogénesis Imperfecta/fisiopatología , Fracturas de la Columna Vertebral/fisiopatología , Adolescente , Adulto , Animales , Densidad Ósea , Calcio/metabolismo , Hueso Esponjoso/diagnóstico por imagen , Hueso Esponjoso/patología , Estudios de Casos y Controles , Recuento de Células , Diferenciación Celular , Niño , Preescolar , Coxa Vara/etiología , Ecocardiografía , Femenino , Perfilación de la Expresión Génica , Genotipo , Cardiopatías/diagnóstico por imagen , Cardiopatías/etiología , Cardiopatías/fisiopatología , Heterocigoto , Humanos , Lactante , Recién Nacido , Canales Iónicos/metabolismo , Vértebras Lumbares/diagnóstico por imagen , Masculino , Ratones , Microscopía Electrónica , Hipotonía Muscular/etiología , Hipotonía Muscular/fisiopatología , Mutación , Tamaño de los Órganos , Osteoblastos/citología , Osteoclastos/citología , Osteogénesis Imperfecta/complicaciones , Osteogénesis Imperfecta/diagnóstico por imagen , Osteogénesis Imperfecta/genética , Fenotipo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Índice de Severidad de la Enfermedad , Espectrometría Raman , Fracturas de la Columna Vertebral/etiología , Adulto Joven
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