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Other entities represented in this entry:
HGNC Approved Gene Symbol: IL1RAPL1
Cytogenetic location: Xp21.3-p21.2 Genomic coordinates (GRCh38) : X:28,587,446-29,956,718 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp21.3-p21.2 | Intellectual developmental disorder, X-linked 21 | 300143 | X-linked recessive | 3 |
The IL1RAPL1 gene encodes a protein with high levels of expression in brain neurons. It participates in the regulation of neurite outgrowth and exocytosis via its interaction with neuronal calcium sensors and the downregulation of calcium channels (Bahi et al., 2003; Gambino et al., 2007). These actions appear to regulate synaptic formation and modulation of synaptic transmission (Piton et al., 2008).
Carrie et al. (1999) demonstrated the importance of interleukin signaling pathways in cognitive function and the normal physiology of the central nervous system. Thorough investigation of a critical region for X-linked mental retardation in Xp22.1-p21.3, they identified a gene, IL1RAPL1, expressed in brain that is responsible for a nonspecific form of X-linked mental retardation (XLID21; 300143), which they called MRX34. The IL1RAPL1 gene encodes a 696-amino acid protein that has homology to IL1RAP (602626). Carrie et al. (1999) found highest Il1rapl1 expression in developing and postnatal mouse hippocampus. Its high level of expression in postnatal brain structures involved in the hippocampal memory system suggested a specialized role for IL1RAPL1 in the physiologic processes underlying memory and learning abilities.
Jin et al. (2000) found that IL1RAPL1 shares 65% identity with IL1RAPL2 (300277) and that both proteins have novel C-terminal sequences not present in other related proteins.
Piton et al. (2008) found Il1rapl1 expression in the cell bodies and growth cones of short, dendrite-like processes in rat hippocampal cells.
Piton et al. (2008) noted that the IL1RAPL1 gene contains 11 exons spanning 1.37 Mb.
Bahi et al. (2003) assessed the effect of recombinant IL1RAPL on the binding affinity of type I IL1R (147810) for its ligands IL1-alpha (147760) and -beta (147720) and searched for proteins interacting with the specific C-terminal domain of IL1RAPL. The authors concluded that IL1RAPL is not a protein receptor for IL1, but interacts with neuronal calcium sensor-1, NCS1 (FREQ; 603315), through its specific C-terminal domain. The functional relevance of IL1RAPL activity was further supported by the inhibitory effect on exocytosis in PC12 cells overexpressing IL1RAPL. The authors suggested that IL1RAPL may regulate calcium-dependent exocytosis.
Gambino et al. (2007) found that stable expression of Il1rapl1 in PC12 cells induced specific silencing of N-type voltage-gated calcium channels (see CACNA1B; 601012) via interaction with Ncs1.
Piton et al. (2008) found that miRNA knockdown of the Il1rapl1 gene in rat hippocampal cells resulted in an increase in the number and length of dendrites.
During the investigation of 3 brothers with a contiguous gene deletion syndrome of Becker muscular dystrophy (300376), glycerol kinase deficiency, congenital adrenal hypoplasia, and mental retardation, Jin et al. (2000) found that the dystrophin gene (300377) was fused tail-to-tail with the IL1RAPL1 gene. The deletion in these patients removed 3 exons encoding the intracellular signaling domain of IL1RAPL1. Jin et al. (2000) suggested that molecules resembling IL1 (see 147720) and IL18 (see 600953) play a role in the development or function of the central nervous system.
In a 6-year-old boy with mental retardation, Lepretre et al. (2003) identified an X chromosome inversion, inv(X)(p21.3q27.1). A similar chromosomal rearrangement was detected in his mildly mentally retarded mother. FISH, using a panel of ordered YAC clones, allowed the identification of YACs spanning both the Xp21.3 and Xq27.1 breakpoints, where many nonspecific mental retardation loci had been reported. Further investigations by FISH showed that the IL1RAPL1 gene at Xp21.3 was disrupted by the inversion.
Bhat et al. (2008) reported a 7-year-old boy with developmental delay, features of autism, facial dysmorphism, and a pericentromeric inversion disrupting the IL1RAPL1 gene: inv(X)(p22.1q13). His mother, who also carried the inversion, had mild mental retardation and autism. She had also experienced a severe CNS infection as an infant.
In affected males from 2 unrelated families with nonspecific X-linked intellectual developmental disorder (XLID21; 300143), Carrie et al. (1999) and Tabolacci et al. (2006) identified mutations in the IL1RAPL1 gene (300206.0001 and 300206.0002).
In 4 affected males in a family segregating nonspecific X-linked intellectual developmental disorder showing linkage to Xp22.11-p21.2 (between markers DXS1226 and DXS1061), Nawara et al. (2008) identified a deletion of exons 2, 3, 4, and 5 in the IL1RAPL1 gene (300206.0003). The deletion was also identified in 3 obligatory female carriers.
In 3 brothers with variable severity of cognitive impairment, ranging from impaired intellectual development to autistic features, Piton et al. (2008) identified a hemizygous 730-kb deletion in the IL1RAPL1 gene (300206.0004). The deletion was identified by whole-genome search of copy number variants using comparative genomic hybridization.
In a French Canadian girl with high functioning autism consistent with Asperger syndrome (see 300143) and no impaired intellectual development, Piton et al. (2008) identified a heterozygous de novo 7-bp deletion (1730delTACTCTT) in exon 9 of the IL1RAPL1 gene, resulting in a frameshift and premature termination. The truncated protein was predicted to lack part of the transmembrane domain as well as the entire cytoplasmic domain. The mutation was not found in 276 control chromosomes. Although in vitro studies in rat hippocampal cells indicated that the deletion resulted in a loss of function, transfection of the truncated mutant alone did not affect neurite outgrowth.
Franek et al. (2011) identified a 635-kb deletion spanning exons 2-5 in the IL1RAPL1 gene (see 300206.0003) in 3 males from a family with X-linked impaired development, although exact deletion breakpoints were not mapped. Two affected males from a second family had a deletion of exons 1-5 of the IL1RAPL1 gene, which was inherited from their unaffected mother. Franek et al. (2011) concluded that loss of function of the IL1RAPL1 protein is associated with intellectual disability.
In a pedigree in which 3 brothers had nonspecific X-linked intellectual developmental disorder (XLID21; 300143), Carrie et al. (1999) found a C-to-A transition in exon 11 (5 nucleotides downstream of the splice acceptor site) that led to conversion of TAC (tyrosine) to TAA (stop).
In 4 affected males from a family with nonspecific X-linked intellectual developmental disorder (XLID21; 300143), Tabolacci et al. (2006) identified a 1460G-A transition in exon 10 of the IL1RAPL1 gene, resulting in a trp487-to-ter (W487X) substitution. The family was originally reported by Kozak et al. (1993) and designated MRX21. The mutation was predicted to result in a truncated protein lacking half of the intracellular TIR domain and the entire C-terminal domain. Two female mutation carriers demonstrated learning disabilities, although blood leukocytes showed X-inactivation patterns favoring the wildtype allele. Tabolacci et al. (2006) suggested that brain neurons may show different X-inactivation patterns.
In 4 affected males in a family segregating nonspecific X-linked intellectual developmental disorder (XLID21; 300143), Nawara et al. (2008) identified a deletion of exons 2, 3, 4, and 5 in the IL1RAPL1 gene. The deletion was also identified in 3 obligatory female carriers, all of whom were apparently of normal intelligence.
Franek et al. (2011) reported a family in which 3 males had low IQ and other variable features, including hypotonia (2), pectus excavatum (2), prominent jaw (2), synophrys (2), and hyperextensible joints (2). Two had behavioral abnormalities, including impulsivity, oppositional disorder, and hyperactivity. One had pigmentary skin changes. Genetic analysis identified a 635-kb deletion spanning exons 2-5 in the IL1RAPL1 gene, similar to that reported by Nawara et al. (2008), although exact deletion breakpoints were not mapped.
In a boy with intellectual developmental disorder (XLID21; 300143), Piton et al. (2008) identified a 730-kb deletion in the IL1RAPL1 gene, resulting in the deletion of exons 3 through 7 and causing premature termination. The deletion was also found in the patient's 2 brothers who had a less severe cognitive phenotype: one had pervasive developmental disorder, not otherwise specified (PDDNOS), and the other had mildly impaired intellectual development with repetitive behaviors, but no other signs of autism. The mother carried the 730-kb deletion but did not show any cognitive or behavioral abnormality.
Bahi, N., Friocourt, G., Carrie, A., Graham, M. E., Weiss, J. L., Chafey, P., Fauchereau, F., Burgoyne, R. D., Chelly, J. IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with neuronal calcium sensor-1 and regulates exocytosis. Hum. Molec. Genet. 12: 1415-1425, 2003. [PubMed: 12783849] [Full Text: https://doi.org/10.1093/hmg/ddg147]
Bhat, S. S., Ladd, S., Grass, F., Spence, J. E., Brasington, C. K., Simensen, R. J., Schwartz, C. E., DuPont, B. R., Stevenson, R. E., Srivastava, A. K. Disruption of the IL1RAPL1 gene associated with a pericentromeric inversion of the X chromosome in a patient with mental retardation and autism. (Letter) Clin. Genet. 73: 94-96, 2008. [PubMed: 18005360] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00920.x]
Carrie, A., Jun, L., Bienvenu, T., Vinet, M.-C., McDonell, N., Couvert, P., Zemni, R., Cardona, A., Van Buggenhout, G., Frints, S., Hamel, B., Moraine, C., and 10 others. A new member of the IL-1 receptor family highly expressed in hippocampus and involved in X-linked mental retardation. Nature Genet. 23: 25-31, 1999. [PubMed: 10471494] [Full Text: https://doi.org/10.1038/12623]
Franek, K. J., Butler, J., Johnson, J., Simensen, R., Friez, M. J., Bartel, F., Moss, T., DuPont, B., Berry, K., Bauman, M., Skinner, C., Stevenson, R. E., Schwartz, C. E. Deletion of the immunoglobulin domain of IL1RAPL1 results in nonsyndromic X-linked intellectual disability associated with behavioral problems and mild dysmorphism. Am. J. Med. Genet. 155A: 1109-1114, 2011. [PubMed: 21484992] [Full Text: https://doi.org/10.1002/ajmg.a.33833]
Gambino, F., Pavlowsky, A., Begle, A., Dupont, J.-L., Bahi, N., Courjaret, R., Gardette, R., Hadjkacem, H., Skala, H., Poulain, B., Chelly, J., Vitale, N., Humeau, Y. IL1-receptor accessory protein-like 1 (IL1RAPL1), a protein involved in cognitive functions, regulates N-type Ca(2+)-channel and neurite elongation. Proc. Nat. Acad. Sci. 104: 9063-9068, 2007. [PubMed: 17502602] [Full Text: https://doi.org/10.1073/pnas.0701133104]
Jin, H., Gardner, R. J., Viswesvaraiah, R., Muntoni, F., Roberts, R. G. Two novel members of the interleukin-1 receptor gene family, one deleted in Xp22.1-Xp21.3 mental retardation. Europ. J. Hum. Genet. 8: 87-94, 2000. [PubMed: 10757639] [Full Text: https://doi.org/10.1038/sj.ejhg.5200415]
Kozak, L., Chiurazzi, P., Genuardi, M., Pomponi, M. G., Zollino, M., Neri, G. Mapping of a gene for non-specific X linked mental retardation: evidence for linkage to chromosomal region Xp21.3-Xp22.1. J. Med. Genet. 30: 866-869, 1993. [PubMed: 8230164] [Full Text: https://doi.org/10.1136/jmg.30.10.866]
Lepretre, F., Delannoy, V., Froguel, P., Vasseur, F., Montpellier, C. Dissection of an inverted X(p21.3q27.1) chromosome associated with mental retardation. Cytogenet. Genome Res. 101: 124-129, 2003. [PubMed: 14610352] [Full Text: https://doi.org/10.1159/000074167]
Nawara, M., Klapecki, J., Borg, K., Jurek, M., Moreno, S., Tryfon, J., Bal, J., Chelly, J., Mazurczak, T. Novel mutation of IL1RAPL1 gene in a nonspecific X-linked mental retardation (MRX) family. Am. J. Med. Genet. 146A: 3167-3172, 2008. [PubMed: 19012350] [Full Text: https://doi.org/10.1002/ajmg.a.32613]
Piton, A., Michaud, J. L., Peng, H., Aradhya, S., Gauthier, J., Mottron, L., Champagne, N., Lafreniere, R. G., Hamdan, F. F., S2D Project Team, Joober, R., Fombonne, E., Marineau, C., Cossette, P., Dube, M.-P., Haghighi, P., Drapeau, P., Barker, P. A., Carbonetto, S., Rouleau, G. A. Mutations in the calcium-related gene IL1RAPL1 are associated with autism. Hum. Molec. Genet. 17: 3965-3974, 2008. [PubMed: 18801879] [Full Text: https://doi.org/10.1093/hmg/ddn300]
Tabolacci, E., Pomponi, M. G., Pietrobono, R., Terracciano, A., Chiurazzi, P., Neri, G. A truncating mutation in the IL1RAPL1 gene is responsible for X-linked mental retardation in the MRX21 family. Am. J. Med. Genet. 140A: 482-487, 2006. [PubMed: 16470793] [Full Text: https://doi.org/10.1002/ajmg.a.31107]