Phenotypic Spectrum in Osteogenesis Imperfecta Due to Mutations in TMEM38B: Unraveling a Complex Cellular Defect.
Recessive mutations in TMEM38B cause type XIV osteogenesis imperfecta (OI) by dysregulating intracellular calcium flux.



Clinical and bone material phenotype description and osteoblast differentiation studies.



Natural history study in pediatric research centers.



Eight patients with type XIV OI.



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.



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.



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.
Department of Endocrinology and Diabetes, Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom.|Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.|Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TH, United Kingdom.
Emma A
EA
Webb
Sheffield Clinical Genetics Service, Sheffield Children's National Health Service Foundation Trust, Sheffield S10 2TH United Kingdom.
Meena
M
Balasubramanian
Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of Wiener Gebietskrankenkasse and Allgemeine Unfallversicherungsanstalt Trama Centre Meidling, First Medical Department, Hanusch Hospital, 1140 Vienna, Austria.
Nadja
N
Fratzl-Zelman
Section on Heritable Disorders of Bone and Extracellular Matrix, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
Wayne A
WA
Cabral
Department of Clinical Genetics, Birmingham Women's Hospital, Birmingham B15 2DG, United Kingdom.
Hannah
H
Titheradge
Department of Clinical Genetics, Birmingham Women's Hospital, Birmingham B15 2DG, United Kingdom.
Atif
A
Alsaedi
Department of Endocrinology and Diabetes, Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom.
Vrinda
V
Saraff
Department of Clinical Genetics, Birmingham Women's Hospital, Birmingham B15 2DG, United Kingdom.
Julie
J
Vogt
Department of Clinical Genetics, Birmingham Women's Hospital, Birmingham B15 2DG, United Kingdom.
Trevor
T
Cole
Department of Clinical Genetics, Birmingham Women's Hospital, Birmingham B15 2DG, United Kingdom.
Susan
S
Stewart
Department of Endocrinology and Diabetes, Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom.
Nicola J
NJ
Crabtree
Section on Heritable Disorders of Bone and Extracellular Matrix, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
Brandi M
BM
Sargent
Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of Wiener Gebietskrankenkasse and Allgemeine Unfallversicherungsanstalt Trama Centre Meidling, First Medical Department, Hanusch Hospital, 1140 Vienna, Austria.
Sonja
S
Gamsjaeger
Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of Wiener Gebietskrankenkasse and Allgemeine Unfallversicherungsanstalt Trama Centre Meidling, First Medical Department, Hanusch Hospital, 1140 Vienna, Austria.
Eleftherios P
EP
Paschalis
Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of Wiener Gebietskrankenkasse and Allgemeine Unfallversicherungsanstalt Trama Centre Meidling, First Medical Department, Hanusch Hospital, 1140 Vienna, Austria.
Paul
P
Roschger
Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of Wiener Gebietskrankenkasse and Allgemeine Unfallversicherungsanstalt Trama Centre Meidling, First Medical Department, Hanusch Hospital, 1140 Vienna, Austria.
Klaus
K
Klaushofer
Department of Endocrinology and Diabetes, Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom.|Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.|Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TH, United Kingdom.
Nick J
NJ
Shaw
Section on Heritable Disorders of Bone and Extracellular Matrix, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
Joan C
JC
Marini
Department of Endocrinology and Diabetes, Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom.|Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.|Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TH, United Kingdom.
Wolfgang
W
Högler
D000293:Adolescent; D000328:Adult; D000818:Animals; D015519:Bone Density; D002118:Calcium / Q000378:metabolism; D000071556:Cancellous Bone / Q000000981:diagnostic imaging / Q000473:pathology; D016022:Case-Control Studies; D002452:Cell Count; D002454:Cell Differentiation; D002648:Child; D002675:Child, Preschool; D060905:Coxa Vara / Q000209:etiology / Q000503:physiopathology*; D004452:Echocardiography; D005260:Female; D020869:Gene Expression Profiling; D005838:Genotype; D006331:Heart Diseases / Q000000981:diagnostic imaging / Q000209:etiology / Q000503:physiopathology; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007473:Ion Channels / Q000235:genetics* / Q000378:metabolism; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D009123:Muscle Hypotonia / Q000209:etiology / Q000503:physiopathology; D009154:Mutation; D009929:Organ Size; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology*; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology*; D010013:Osteogenesis Imperfecta / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology*; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index; D013059:Spectrum Analysis, Raman; D016103:Spinal Fractures / Q000209:etiology / Q000503:physiopathology*; D055815:Young Adult
D007473:Ion Channels; C578840:TMEM38B protein, human; C522222:TRIC-B protein, mouse; D002118:Calcium