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TMEM67
transmembrane protein 67
TMEM67 is located on the long (q) arm of chromosome 8, at band 8q22.1. Arm ratio per GRCh38 - banding schematic.
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Overview
TMEM67 is located on chromosome 8 and produces a 995-amino-acid protein that resides within the membrane of primary cilia. These slender, hair-like organelles act as cellular antennae, detecting external signals and regulating developmental programmes during embryonic growth. The TMEM67 protein contributes to ciliary assembly and signal transduction, particularly pathways that govern tissue patterning in the developing brain and kidneys.
When both copies of TMEM67 carry pathogenic variants, individuals develop ciliopathies characterised by malformations of the cerebellum, cystic kidney disease, and additional structural abnormalities. The gene is recognised on multiple NHS Genomic Medicine Service panels for conditions affecting kidney, brain, and eye development, reflecting its broad developmental importance.
What the gene does
The TMEM67 protein is embedded in the ciliary membrane and participates in maintaining the structural integrity and functional competence of primary cilia. Cilia serve as signalling hubs, relaying information from growth factors and morphogens into the cell to orchestrate gene expression programmes during development. TMEM67 contributes to the correct localisation of other ciliary proteins and helps regulate trafficking of molecules into and out of the ciliary compartment.
During embryogenesis, proper ciliary function is essential for establishing left-right body asymmetry, patterning the neural tube, and guiding kidney tubule formation. The TMEM67 protein appears particularly important for cerebellar development and for preventing abnormal cyst formation in renal tubules. Loss of TMEM67 function disrupts these signalling networks, leading to the characteristic brain malformations and polycystic kidneys seen in affected individuals. The protein's role extends to other tissues, including the retina and limb buds, where ciliary signalling coordinates cell differentiation and tissue architecture.
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Chromosome location
TMEM67 is located on the long arm of chromosome 8 at position 8q22.1. This chromosomal region contains multiple genes involved in developmental processes. The gene spans a substantial genomic interval and is transcribed into messenger RNA that directs synthesis of the 995-amino-acid transmembrane protein. Structural features of the genomic locus have not been extensively characterised in public databases.
Protein structure
The TMEM67 protein consists of 995 amino acids and contains several predicted functional regions. A cysteine-rich region spans amino acids 37 through 280, which may participate in protein folding or interactions with other ciliary components. Towards the C-terminus, a coiled-coil domain extends from amino acids 828 to 917; coiled-coil structures typically mediate protein-protein interactions and may help anchor TMEM67 within multiprotein complexes at the ciliary membrane. The protein features multiple predicted transmembrane helices that allow it to span the lipid bilayer, positioning different segments inside and outside the ciliary compartment to facilitate its trafficking and signalling functions.
Key variants
Pathogenic variants in TMEM67 follow an autosomal recessive inheritance pattern, meaning affected individuals carry alterations in both gene copies. Variants include missense changes that alter single amino acids, nonsense mutations that introduce premature stop codons, and frameshift or splice-site alterations that disrupt protein production. The severity and specific features of the resulting ciliopathy can vary depending on which variants are inherited and how severely they compromise protein function.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Biallelic pathogenic variants in TMEM67 cause ciliopathies with a spectrum of severity. Joubert syndrome is characterised by a distinctive brain malformation called the molar tooth sign on imaging, developmental delay, abnormal eye movements, and breathing irregularities in infancy; many affected individuals also develop cystic kidney disease. Meckel-Gruber syndrome represents a more severe presentation with occipital encephalocele, enlarged cystic kidneys, and polydactyly, typically resulting in perinatal lethality. The phenotypic overlap reflects shared underlying defects in ciliary signalling, with different variant combinations influencing clinical outcomes.
Inheritance pattern
Conditions caused by pathogenic TMEM67 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
TMEM67 holds green-rated (high-confidence) status on numerous NHS Genomic Medicine Service gene panels, reflecting robust evidence linking the gene to inherited disease. It appears on panels for Bardet Biedl syndrome, cystic kidney disease, ductal plate malformation, foetal anomalies, intellectual disability, limb disorders, neurological ciliopathies, ophthalmological ciliopathies, rare multisystem ciliopathy disorders, renal ciliopathies, structural eye disease, tubulointerstitial kidney disease, and unexplained kidney failure in young people. This extensive panel membership underscores the gene's relevance across multiple clinical pathways and its importance in diagnosing individuals with complex, multi-organ developmental conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What inheritance pattern does TMEM67 follow?
TMEM67-related conditions are inherited in an autosomal recessive manner. An affected individual inherits one pathogenic variant from each parent, who are typically unaffected carriers.
Why does TMEM67 dysfunction affect multiple organs?
Primary cilia are present on cells throughout the body and coordinate signalling pathways essential for development. When TMEM67 function is lost, ciliary defects disrupt patterning in the brain, kidneys, eyes, and other tissues during embryogenesis.
Can TMEM67 variants cause milder symptoms than Joubert or Meckel-Gruber syndrome?
The clinical spectrum associated with TMEM67 variants ranges from severe perinatal presentations to Joubert syndrome with variable renal and ocular involvement. Phenotype severity depends on the specific variants inherited and their impact on protein function.