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Cell Calcium. 2019 Nov 13;85:102110. doi: 10.1016/j.ceca.2019.102110. [Epub ahead of print]

STIM1 R304W in mice causes subgingival hair growth and an increased fraction of trabecular bone.

Author information

1
Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
2
Faculty of Veterinary Medicine, Norwegian University of Life Sciences, Norway.
3
Department of Orthodontics, Institute of Clinical Dentistry, University of Oslo, Oslo, Norway.
4
Department of Biomaterials, Institute of Clinical Dentistry, University of Oslo, Oslo, Norway.
5
Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway.
6
Neurology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Neuroscience Section, Department of Pathophysiology and Transplantation, Dino Ferrari Centre, University of Milan, Milan, Italy.
7
Department of Neurology, Nakamura Memorial Hospital, Sapporo, Japan.
8
CHRU, Hôpital Gui de Chauliac, Montpellier, France.
9
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma, USA.
10
Department of Haematology, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
11
Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, USA.
12
Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway. Electronic address: eirik.frengen@medisin.uio.no.

Abstract

Calcium signaling plays a central role in bone development and homeostasis. Store operated calcium entry (SOCE) is an important calcium influx pathway mediated by calcium release activated calcium (CRAC) channels in the plasma membrane. Stromal interaction molecule 1 (STIM1) is an endoplasmic reticulum calcium sensing protein important for SOCE. We generated a mouse model expressing the STIM1 R304W mutation, causing Stormorken syndrome in humans. Stim1R304W/R304W mice showed perinatal lethality, and the only three animals that survived into adulthood presented with reduced growth, low body weight, and thoracic kyphosis. Radiographs revealed a reduced number of ribs in the Stim1R304W/R304W mice. Microcomputed tomography data revealed decreased cortical bone thickness and increased trabecular bone volume fraction in Stim1R304W/R304W mice, which had thinner and more compact bone compared to wild type mice. The Stim1R304W/+ mice showed an intermediate phenotype. Histological analyses showed that the Stim1R304W/R304W mice had abnormal bone architecture, with markedly increased number of trabeculae and reduced bone marrow cavity. Homozygous mice showed STIM1 positive osteocytes and osteoblasts. These findings highlight the critical role of the gain-of-function (GoF) STIM1 R304W protein in skeletal development and homeostasis in mice. Furthermore, the novel feature of bilateral subgingival hair growth on the lower incisors in the Stim1R304W/R304W mice and 25 % of the heterozygous mice indicate that the GoF STIM1 R304W protein also induces an abnormal epithelial cell fate.

KEYWORDS:

Abnormal bone architecture; Ectopic hair growth; STIM1 R304W; Skeletal defects; Stormorken syndrome

PMID:
31785581
DOI:
10.1016/j.ceca.2019.102110

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