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INVS
inversin
INVS is located on the long (q) arm of chromosome 9, at band 9q31.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The INVS gene encodes inversin, a protein localised to the primary cilium and basal body of cells throughout the body. Primary cilia are microscopic, antenna-like projections that detect chemical and mechanical signals, coordinating cellular behaviour during development and tissue maintenance. Inversin participates in establishing the correct architecture of the cilium and regulating signalling pathways that control cell division, differentiation, and migration.
Pathogenic variants in INVS are inherited in an autosomal recessive pattern, meaning two altered copies (one from each parent) are required for disease to manifest. Loss of inversin function disrupts ciliary signalling, particularly affecting tissues where cilia perform critical roles such as the kidneys, liver, and developing organs. These disruptions underlie a spectrum of ciliopathies characterised by cystic kidney disease, liver fibrosis, and developmental anomalies.
What the gene does
Inversin functions primarily at the base and within the axoneme of the primary cilium, where it coordinates several distinct cellular processes. The protein contributes to planar cell polarity, a developmental mechanism ensuring that epithelial cells align correctly across tissue planes. This polarity is essential for normal kidney tubule formation and left-right body axis determination during embryogenesis.
Inversin also modulates Wnt signalling, a pathway controlling cell fate decisions and proliferation. By influencing the balance between canonical and non-canonical Wnt pathways, inversin helps regulate the transition from cell proliferation to differentiation in developing tissues. Evidence suggests the protein participates in ciliary membrane trafficking, ensuring that signalling receptors and structural components reach their correct positions within the cilium. When inversin is absent or non-functional, cells exhibit shortened or malformed cilia, abnormal cell division patterns, and impaired responses to extracellular cues that normally guide tissue architecture.
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Chromosome location
INVS is located on chromosome 9 at cytogenetic band 9q31.1. This region lies on the long arm of chromosome 9, approximately one-third of the distance from the centromere to the telomere. The gene spans multiple exons encoding a 1,065 amino acid protein, though the precise exon structure varies slightly between transcript isoforms.
Protein structure
The inversin protein comprises 1,065 amino acids and is characterised by an extensive array of ankyrin (ANK) repeats spanning much of its length. These repeats include ANK 1 (amino acids 13-42), ANK 2 (47-76), ANK 3 (80-110), ANK 4 (113-144), ANK 5 (148-177), ANK 6 (181-213), ANK 7 (220-250), ANK 8 (254-283), ANK 9 (288-317), ANK 10 (321-350), ANK 11 (356-385), ANK 12 (389-418), ANK 13 (422-451), ANK 14 (455-484), and ANK 15 (488-517).
Ankyrin repeats typically form stacked helix-turn-helix motifs that mediate protein-protein interactions. In inversin, this extended ANK repeat region likely serves as a scaffold, binding multiple ciliary and signalling proteins to coordinate their activity at the cilium base and within the cytoplasm.
Key variants
Pathogenic variants in INVS are distributed across the gene, with both missense changes and truncating variants (nonsense, frameshift, splice-site) reported in affected individuals. Truncating variants often result in complete loss of protein function, whilst missense variants may disrupt specific interactions mediated by the ankyrin repeat region. The severity and specific features of ciliopathy can vary depending on the nature and position of the variants, though genotype-phenotype correlations remain incompletely defined.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1367del | p.Gly456fs | Pathogenic/Likely pathogenic | ★★☆☆ | Nephronophthisis |
c.1726C>T | p.Arg576Ter | Pathogenic | ★★☆☆ | INVS-related disorders |
c.2160del | p.Ser721fs | Pathogenic/Likely pathogenic | ★★☆☆ | Nephronophthisis |
c.2225dup | p.Lys743fs | Pathogenic/Likely pathogenic | ★★☆☆ | Nephronophthisis |
c.2449dup | p.Glu817fs | Pathogenic/Likely pathogenic | ★★☆☆ | Nephronophthisis |
c.2614C>T | p.Gln872Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Nephronophthisis |
c.2747dup | p.Asn917fs | Pathogenic/Likely pathogenic | ★★☆☆ | INVS-related disorder |
c.2870_2871dup | p.Thr958fs | Pathogenic/Likely pathogenic | ★★☆☆ | Infantile nephronophthisis |
c.2894G>A | p.Trp965Ter | Pathogenic/Likely pathogenic | ★★☆☆ | INVS-related disorders |
c.648G>A | p.Trp216Ter | Pathogenic | ★★☆☆ | Nephronophthisis |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Biallelic pathogenic variants in INVS cause nephronophthisis type 2, an early-onset form of cystic kidney disease typically presenting in infancy or early childhood. Affected individuals develop progressive kidney dysfunction, often accompanied by liver fibrosis and cardiovascular anomalies. The condition forms part of a broader ciliopathy spectrum, as INVS dysfunction disrupts multiple ciliary signalling pathways essential for normal organ development.
Some individuals with INVS variants exhibit features overlapping with other ciliopathies, including situs inversus (reversed organ positioning) and developmental anomalies affecting the central nervous system or skeleton. The multisystem nature of these presentations reflects the widespread importance of primary cilia during embryonic patterning and postnatal tissue homeostasis.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic INVS 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
INVS is included on multiple NHS Genomic Medicine Service gene panels reflecting its role in kidney and multisystem ciliopathies. It holds green classification (high evidence for clinical validity) on the Cystic kidney disease, Rare multisystem ciliopathy disorders, Renal ciliopathies, Tubulointerstitial kidney disease, and Unexplained kidney failure in young people panels. The gene also appears on the Fetal anomalies and Neonatal cholestasis panels, both with green status, recognising the potential for prenatal or early-life presentation. These panel memberships facilitate diagnostic sequencing for patients presenting with relevant clinical features within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What inheritance pattern does INVS follow?
INVS-related conditions are inherited in an autosomal recessive manner. An individual must inherit two pathogenic variants (one from each parent) to develop disease. Parents who each carry one variant typically remain unaffected.
At what age do INVS-related kidney problems typically appear?
Nephronophthisis type 2 caused by INVS variants generally presents in infancy or early childhood, often earlier than other forms of nephronophthisis. Progressive kidney dysfunction may lead to end-stage kidney disease within the first decade of life, though individual trajectories vary.
Why does INVS dysfunction affect multiple organ systems?
Inversin functions in primary cilia, which are present on cells throughout the body and coordinate diverse signalling pathways during development and tissue maintenance. Disruption of ciliary function impacts any organ relying on these signals, particularly the kidneys, liver, cardiovascular system, and developing embryonic structures.