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TMEM231
transmembrane protein 231
TMEM231 is located on the long (q) arm of chromosome 16, at band 16q23.1. Arm ratio per GRCh38 - banding schematic.
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Overview
TMEM231 encodes transmembrane protein 231, a component of the ciliary transition zone that serves as a selective barrier controlling molecular entry into the primary cilium. Primary cilia are antenna-like structures projecting from cell surfaces that detect signals from the environment and coordinate developmental pathways. The transition zone acts as a quality-control gate, ensuring only appropriate proteins enter the ciliary compartment whilst excluding others. When TMEM231 function is compromised, this gatekeeping mechanism fails, leading to abnormal ciliary composition and disrupted signalling during embryonic development and tissue maintenance. Pathogenic variants in this gene follow an autosomal recessive inheritance pattern and cause severe ciliopathies characterised by brain malformations, kidney cysts, skeletal abnormalities, and retinal dysfunction.
What the gene does
The TMEM231 protein functions as a structural and regulatory component of the ciliary transition zone, the compartment connecting the ciliary axoneme to the basal body. This region orchestrates the selective passage of proteins into and out of the cilium, maintaining the distinct biochemical environment necessary for proper ciliary signalling. TMEM231 helps anchor transition zone complexes to the ciliary membrane, stabilising the diffusion barrier that prevents inappropriate mixing of ciliary and cytoplasmic contents. During embryogenesis, properly functioning cilia relay signals from the Sonic Hedgehog pathway and other morphogen gradients, which pattern the developing brain, limbs, and internal organs. Loss of TMEM231 disrupts these developmental cascades, particularly affecting structures that depend on precise left-right patterning and midline formation. The protein appears particularly crucial for neuronal migration and cerebellar development, as well as for maintaining photoreceptor outer segments in the retina and renal tubule architecture in the kidneys.
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Chromosome location
TMEM231 is located on the long arm of chromosome 16 at position 23.1 (16q23.1). The gene spans approximately 9.5 kilobases of genomic DNA and contains six exons. This chromosomal region has moderate gene density, with several other genes in the vicinity contributing to diverse cellular processes unrelated to ciliary function.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. The 316-amino-acid TMEM231 protein contains multiple predicted transmembrane helices that anchor it within ciliary membranes, but specific functional domains remain to be mapped through structural studies. The precise topology and orientation of the transmembrane segments relative to the ciliary membrane are subjects of ongoing investigation.
Key variants
Pathogenic variants in TMEM231 are predominantly loss-of-function changes including nonsense mutations, frameshift deletions or insertions, and splice-site alterations that severely reduce or eliminate protein production. Missense variants affecting conserved residues within predicted transmembrane regions have also been reported in affected individuals. The spectrum of clinical severity correlates broadly with the degree of residual protein function, with complete loss typically associated with lethal Meckel syndrome phenotypes and hypomorphic variants sometimes permitting survival with Joubert syndrome features.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
TMEM231-related ciliopathies encompass a phenotypic continuum ranging from perinatally lethal Meckel syndrome to the more viable Joubert syndrome. Meckel syndrome presents with occipital encephalocele, multicystic kidney dysplasia, polydactyly, and hepatic developmental defects, typically incompatible with prolonged survival. Joubert syndrome features a characteristic cerebellar and brainstem malformation known as the molar tooth sign on brain imaging, accompanied by breathing abnormalities, developmental delay, and variable involvement of the kidneys and retina. The clinical overlap between these conditions reflects shared disruption of ciliary signalling during organogenesis, with the specific combination and severity of features varying between affected families.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic TMEM231 variants typically follow autosomal recessive or autosomal dominant inheritance.
Carrier frequency by population How common is heterozygous TMEM231 carrier status across ancestry groups?UK clinical status
TMEM231 appears on multiple NHS Genomic Medicine Service gene panels with green classification, reflecting robust evidence for clinical validity. It is included in the Fetal Anomalies panel, Neurological Ciliopathies panel, Ophthalmological Ciliopathies panel, Rare Multisystem Ciliopathy Disorders panel, Renal Ciliopathies panel, Retinal Disorders panel, and Skeletal Dysplasia panel. This extensive panel membership underscores the gene's relevance across prenatal diagnostics and postnatal evaluation of individuals with multisystem features consistent with ciliopathy.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
How are TMEM231 variants inherited?
TMEM231-related conditions follow an autosomal recessive inheritance pattern, meaning an individual must inherit pathogenic variants from both parents to develop disease. Carrier parents each have one working copy and typically show no symptoms.
Can TMEM231 variants be detected prenatally?
Yes, when both parental variants are known, prenatal or preimplantation genetic testing can be offered to at-risk families. Fetal ultrasound may also detect structural anomalies associated with TMEM231-related ciliopathies during routine pregnancy screening.
Why does TMEM231 disruption affect so many different organs?
Primary cilia are present on nearly all cell types during development, acting as signalling hubs that coordinate tissue patterning. When transition zone proteins like TMEM231 fail, multiple organ systems that rely heavily on ciliary signals during embryogenesis are affected simultaneously, producing the multisystem features characteristic of ciliopathies.