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TMEM138
transmembrane protein 138
TMEM138 is located on the long (q) arm of chromosome 11, at band 11q12.2. Arm ratio per GRCh38 - banding schematic.
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Overview
TMEM138 (transmembrane protein 138) is located on chromosome 11q12.2 and encodes a 162-amino-acid protein integral to the structure and function of primary cilia. Cilia are microscopic projections found on the surface of most human cells, where they detect chemical signals and coordinate developmental pathways. Disruption of TMEM138 impairs ciliary assembly, resulting in a spectrum of multisystem disorders collectively known as ciliopathies. These conditions affect the brain, kidneys, eyes, and other organs during foetal development and childhood. TMEM138-related ciliopathy is inherited in an autosomal recessive pattern, meaning that two pathogenic variants (one from each parent) are required for disease to manifest. The gene is assessed in UK carrier screening programmes to identify individuals who carry a single variant and may be at risk of having affected children if their partner also carries a pathogenic change in the same gene.
What the gene does
The TMEM138 protein localises to the base of primary cilia and participates in the trafficking of proteins required for ciliary assembly and maintenance. Cilia serve as sensory antennae, detecting extracellular signals such as growth factors and morphogens that guide tissue patterning during embryonic development. The protein helps coordinate intraflagellar transport, the bidirectional movement of cargo along the ciliary axoneme. This transport process is essential for delivering structural components and signalling molecules to the cilium tip and removing degradation products. Loss of TMEM138 function disrupts the ciliary architecture, impairing Hedgehog and Wnt signalling pathways that regulate cell proliferation, differentiation, and organ morphogenesis. Consequently, affected individuals exhibit developmental anomalies in organs that rely heavily on intact ciliary signalling, including the cerebellum, retina, and renal tubules. The protein's role in ciliogenesis appears particularly critical during foetal development, when ciliary signalling coordinates brain regionalisation and kidney tubule formation.
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Chromosome location
TMEM138 is located on the long arm of chromosome 11 at band 11q12.2. The genomic region encompasses multiple exons encoding the 162-amino-acid protein. This chromosomal band lies within a region containing several other genes involved in development and cellular signalling. The precise exon-intron architecture contributes to the gene's regulation, with variants in both coding and splice-site regions reported to cause disease.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. TMEM138 is predicted to contain multiple transmembrane helices that anchor it within cellular membranes, consistent with its role in ciliary membrane structures. The protein's small size and membrane-spanning topology suggest it functions as a structural or regulatory component within multiprotein complexes at the ciliary base, rather than possessing intrinsic enzymatic activity.
Key variants
Pathogenic variants in TMEM138 include missense changes, frameshift deletions, and splice-site alterations that reduce or abolish protein function. Because the condition follows autosomal recessive inheritance, individuals with a single pathogenic variant are carriers and typically unaffected. Compound heterozygosity, where two different pathogenic variants are inherited (one from each parent), is commonly observed in affected individuals. Variant classification relies on functional studies demonstrating impaired ciliary assembly or localisation, combined with segregation analysis in affected families.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Biallelic pathogenic variants in TMEM138 cause Joubert syndrome type 16, a severe ciliopathy characterised by a distinctive brain malformation known as the molar tooth sign, observable on magnetic resonance imaging. Affected individuals present with hypotonia, developmental delay, irregular breathing patterns in infancy, and intellectual disability. Additional features may include retinal dystrophy leading to vision impairment, kidney cysts, and polydactyly. The severity and combination of features vary between individuals, even within the same family, reflecting the complexity of ciliary signalling during development.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic TMEM138 variants typically follow autosomal recessive or autosomal dominant inheritance.
Carrier frequency by population How common is heterozygous TMEM138 carrier status across ancestry groups?UK clinical status
TMEM138 is included on multiple NHS Genomic Medicine Service gene panels as a green-rated gene, indicating strong evidence for clinical actionability. These panels include Fetal anomalies, Neurological ciliopathies, Ophthalmological ciliopathies, Rare multisystem ciliopathy disorders, and Renal ciliopathies. Green classification signifies that the gene meets evidence thresholds for diagnostic testing within the NHS, supporting its use in prenatal diagnosis and postnatal evaluation of individuals with ciliopathy phenotypes. Inclusion across multiple panels reflects the multisystem nature of TMEM138-related disease.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does it mean to be a carrier of a TMEM138 variant?
Carriers have one pathogenic variant and one normal copy of the gene, which is sufficient for normal ciliary function. Carriers do not develop ciliopathy symptoms but may have an affected child if their partner is also a carrier of a variant in TMEM138.
How is TMEM138-related ciliopathy diagnosed?
Diagnosis combines clinical features such as the molar tooth sign on brain imaging with genetic testing to identify biallelic pathogenic variants. Prenatal diagnosis is available for families with a known variant through chorionic villus sampling or amniocentesis.
Can TMEM138 variants cause milder forms of disease?
The spectrum of TMEM138-related ciliopathy severity varies, with some individuals exhibiting predominantly neurological features and others presenting with multisystem involvement. Genotype-phenotype correlations remain under investigation, and clinical outcomes cannot be reliably predicted from genetic findings alone.