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TMEM38B
transmembrane protein 38B
TMEM38B is located on the long (q) arm of chromosome 9, at band 9q31.2. Arm ratio per GRCh38 - banding schematic.
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Overview
TMEM38B encodes transmembrane protein 38B, a member of the TMEM38 family of intracellular calcium channel regulators. The protein plays a role in maintaining calcium balance within the endoplasmic reticulum, the cellular compartment responsible for protein folding and calcium storage. Proper calcium regulation is essential for numerous cellular processes, including bone mineralisation and skeletal development. When both copies of TMEM38B carry pathogenic variants, individuals may develop skeletal abnormalities due to disrupted calcium signalling in bone-forming cells. The gene is located on chromosome 9 and produces a protein of 291 amino acids that spans cellular membranes multiple times.
What the gene does
Transmembrane protein 38B functions as a calcium channel or channel regulator within the endoplasmic reticulum membrane. The protein facilitates calcium ion movement across this internal membrane, contributing to the regulation of intracellular calcium stores. Calcium ions serve as critical signalling molecules in osteoblasts and osteocytes, the cells responsible for bone formation and maintenance. By modulating calcium release from the endoplasmic reticulum, TMEM38B influences cellular responses to signals that direct bone development and remodelling. The protein's transmembrane architecture allows it to sense changes in calcium concentration on both sides of the endoplasmic reticulum membrane. Disruption of this regulatory function impairs the calcium-dependent processes required for normal skeletal mineralisation and bone matrix organisation. Research suggests that TMEM38B works in coordination with other calcium regulatory proteins to maintain the precise calcium gradients necessary for proper cellular function.
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Chromosome location
TMEM38B is located on the long arm of chromosome 9 at position 9q31.2. This chromosomal region contains multiple genes involved in various cellular processes. The specific genomic coordinates place TMEM38B within a gene-dense area, though the gene itself is relatively compact compared to many human genes. The chromosomal location has been consistently mapped across reference genome assemblies.
Protein structure
The TMEM38B protein consists of 291 amino acids and contains multiple transmembrane segments that anchor it within the endoplasmic reticulum membrane. The protein's architecture enables it to span the membrane several times, creating a structure capable of forming or regulating an ion channel. A disordered region extends from amino acid 256 to 291 at the C-terminus. Disordered regions lack fixed three-dimensional structure and often serve regulatory functions, mediating protein-protein interactions or post-translational modifications that modulate channel activity. The transmembrane topology positions portions of the protein on both the cytoplasmic and luminal sides of the endoplasmic reticulum membrane, allowing it to respond to signals from both compartments.
Key variants
Pathogenic variants in TMEM38B follow an autosomal recessive inheritance pattern, meaning affected individuals carry variants in both gene copies. These variants typically result in loss of protein function, either through premature termination, destabilisation of the protein structure, or disruption of the transmembrane domains essential for channel activity. The functional consequences manifest primarily in skeletal tissues, where calcium regulation is particularly critical for bone formation and mineralisation.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Biallelic pathogenic variants in TMEM38B cause autosomal recessive skeletal disorders characterised by bone fragility and abnormal skeletal development. These conditions may present with features overlapping osteogenesis imperfecta, including increased fracture susceptibility, bone deformity, and reduced bone mineral density. The severity and specific clinical features vary depending on the nature and location of the pathogenic variants. Skeletal abnormalities may be detected prenatally through imaging or become apparent in early childhood. Clinical management typically involves orthopaedic monitoring and interventions to prevent fractures and support bone health.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic TMEM38B variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
TMEM38B is included on multiple NHS Genomic Medicine Service gene panels. The gene holds green classification status on the Fetal Anomalies panel (R21), Osteogenesis Imperfecta panel (R102), and Skeletal Dysplasia panel (R104). Green classification indicates strong evidence supporting the gene-disease relationship, meaning TMEM38B variants are considered diagnostically relevant in the NHS genomic testing pathway for individuals with skeletal abnormalities detected prenatally or postnatally.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does autosomal recessive inheritance mean for TMEM38B?
Autosomal recessive inheritance means that an individual must inherit a pathogenic variant from both parents to develop a TMEM38B-related condition. Carriers with one variant copy typically do not show symptoms. When both parents are carriers, each child has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither variant.
How do TMEM38B variants affect calcium regulation?
Pathogenic variants in TMEM38B disrupt the protein's ability to regulate calcium release from the endoplasmic reticulum. This impairs calcium signalling in bone-forming cells, affecting processes essential for normal skeletal development and mineralisation. The resulting calcium dysregulation contributes to bone fragility and structural abnormalities.
Can TMEM38B-related skeletal conditions be detected before birth?
Yes, some skeletal abnormalities associated with TMEM38B variants may be visible on prenatal ultrasound or other imaging studies. TMEM38B is included on the NHS Fetal Anomalies panel, reflecting its relevance in prenatal diagnosis when skeletal dysplasia features are identified during pregnancy.