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IL1RAPL1
interleukin 1 receptor accessory protein like 1
IL1RAPL1 is located on the short (p) arm of chromosome X, at band Xp21.3-p21.2. Arm ratio per GRCh38 - banding schematic.
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Overview
IL1RAPL1 (interleukin 1 receptor accessory protein like 1) is situated on the short arm of the X chromosome and encodes a transmembrane protein involved in neuronal development. Despite its name suggesting similarity to interleukin-1 signalling components, the protein functions primarily in the central nervous system rather than the immune system.
Variants that disrupt IL1RAPL1 function have been identified in individuals with intellectual disability, often accompanied by behavioural features. The X-linked location means males are typically more severely affected than females, though the inheritance pattern can vary depending on the specific variant and family history. Understanding this gene's role has contributed to knowledge of the molecular mechanisms underlying neurodevelopmental conditions.
What the gene does
The IL1RAPL1 protein is expressed predominantly in the brain, where it localises to synapses - the junctions between nerve cells. Research indicates the protein participates in synapse formation and maturation during brain development, influencing how neurons connect and communicate.
The protein appears to function as a cell-surface receptor that interacts with molecules on neighbouring cells, coordinating signals that shape neuronal architecture. Studies suggest IL1RAPL1 activity affects dendritic spine formation, the tiny protrusions on neurons that receive incoming signals. By modulating these structures, the protein influences synaptic strength and plasticity, processes fundamental to learning and memory.
Evidence also suggests IL1RAPL1 may regulate the balance of excitatory neurotransmission in developing neural circuits, contributing to the establishment of normal brain connectivity patterns during early development.
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Chromosome location
IL1RAPL1 maps to chromosome band Xp21.3-p21.2 on the short arm of the X chromosome. This chromosomal region has been associated with neurodevelopmental phenotypes in deletion studies.
The X-chromosomal location has implications for inheritance patterns, as males possess only one X chromosome whilst females have two. Genomic structural features in this region can influence gene expression, though detailed exon counts and transcript variants have not been fully characterised in all databases.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Pathogenic variants in IL1RAPL1 include both loss-of-function changes (such as nonsense variants and deletions) and missense substitutions that alter protein structure. The spectrum of documented variants reflects the gene's role in neurodevelopment, with changes typically resulting in reduced or absent protein function.
Because IL1RAPL1 resides on the X chromosome, variant interpretation considers X-inactivation patterns in females and hemizygous status in males. Variant pathogenicity assessment draws on computational predictions, family segregation data, and phenotypic correlation.
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.1054C>T | p.Arg352Ter | Pathogenic | ★★☆☆ | Intellectual disability, X-linked 21 |
c.148C>T | p.Arg50Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Intellectual disability, X-linked 21 |
GRCh37/hg19 Xp21.3-21.2(chrX:29007766-29734333)x0 | - | Pathogenic | ★☆☆☆ | not provided |
GRCh37/hg19 Xp21.3(chrX:28493281-29234189)x1 | - | Pathogenic | ★☆☆☆ | not provided |
GRCh37/hg19 Xp21.3(chrX:28780078-28893971)x0 | - | Pathogenic | ★☆☆☆ | not provided |
g.(?_29414355)_(29417445_?)del | - | Pathogenic | ★☆☆☆ | not provided |
c.1027C>T | p.Arg343Ter | Pathogenic | ★☆☆☆ | Intellectual disability, X-linked 21 |
c.1239dup | p.Val414fs | Pathogenic | ★☆☆☆ | not provided |
c.555C>A | p.Cys185Ter | Pathogenic | ★☆☆☆ | not provided |
c.660T>A | p.Tyr220Ter | Pathogenic | ★☆☆☆ | Inborn genetic diseases |
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
Pathogenic IL1RAPL1 variants are principally associated with intellectual disability, which may range from mild to moderate severity. Affected individuals often exhibit delayed speech and language development, with some showing features overlapping with autism spectrum disorder.
Behavioural characteristics can include attention difficulties and social communication challenges. The clinical presentation varies considerably between individuals, even within the same family, reflecting differences in genetic background and possibly environmental factors. Females carrying pathogenic variants may be unaffected, mildly affected, or display features comparable to affected males, depending on X-inactivation patterns.
No disease links recorded for this gene in our reference set.
UK clinical status
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
Why does IL1RAPL1 primarily affect brain function despite its name suggesting immune involvement?
Although IL1RAPL1 shares structural similarity with interleukin-1 receptor accessory proteins, it has evolved a distinct role in the nervous system. The protein is predominantly expressed in brain tissue and functions in synaptic development rather than immune signalling.
How does the X-chromosomal location of IL1RAPL1 affect inheritance?
Males, having only one X chromosome, typically show more pronounced effects from pathogenic variants. Females may be unaffected carriers, though some experience features depending on random X-inactivation patterns in their cells.
Can the severity of intellectual disability be predicted from the type of IL1RAPL1 variant?
Clinical severity varies considerably between individuals, even with the same variant. While complete loss of protein function often correlates with more significant impairment, individual outcomes depend on multiple genetic and environmental factors that cannot be precisely predicted from variant type alone.