A truncating mutation in the IL1RAPL1 gene is responsible for X‐linked mental retardation in the MRX21 family

Abstract

X-linked mental retardation (XLMR) is a genetically heterogeneous condition, due to mutations in at least 50 genes, involved in functioning of the central nervous system and located on the X chromosome. Nonspecific XLMR (MRX) is characterized essentially by mental retardation transmitted by X-linked inheritance. More than 80 extended MRX pedigrees have been reported to date, which have been distinguished exclusively by physical position of the corresponding gene on the X chromosome, established by linkage analysis. One such family, MRX21, which was described by us in 1993 and localized to Xp11.4-pter, has now been reanalyzed with additional markers and after one more affected individual had became available. This extra information allowed a significant reduction of the linkage interval and, eventually, identification of the mutant gene. A stop mutation in exon 10 of the IL1RAPL1 gene (in Xp21) was found in the four affected males and in obligate carriers, allowing conclusive counseling of other family members of uncertain carrier status. The W487X mutation results in the production of a truncated IL1RAPL protein, comprised of the extracellular Ig-like domain and transmembrane tract, but lacking the last 210 aminoacids of the cytoplasmic domain. MRX21 is the first extended MRX family with a point mutation in IL1RAPL1 and the second with a stop mutation, which had been previously found only in a small family. Our report confirms the role of the IL1RAPL1 gene in causing nonspecific mental retardation in males and underlines the importance of detailed linkage analysis before candidate gene mutational screening.

Novel mutation of IL1RAPL1 gene in a nonspecific X‐linked mental retardation (MRX) family

“…Besides few different deletions, one mutation introducing a stop codon p.Y459X in exon 10 was reported [Carrie et al, 1999] and another mutation in the same exon p.W487X was recently published in MRX21 family [Tabolacci et al, 2006]. Both mutations cause the production of a truncated protein lacking half of the intracellular TIR domain and the entire C-terminal domain.…”

“…Carrie et al [1999] mapped microdeletions in this chromosome region in six patients (two with MR, four with MR and adrenal hypoplasia (DAX1) or adrenal hypoplasia and glycerol kinase deficiency (GKD) syndromes (GK)). Tabolacci et al [2006] postulated that this genomic region must be particularly prone to nonhomologous recombination, because some pericentric inversions have also been characterized to interrupt the IL1RAPL1 gene, causing MR in a male [Lepretre et al, 2003] and possibly in a female [Laumonnier et al, 2002] patients.…”

<i>DMD</i> and <i>IL1RAPL1</i>: two large adjacent genes localized within a common fragile site (FRAXC) have reduced expression in cultured brain tumors

“…The IL1RAPL1 gene and DMD were found to be deleted in a family with Becker muscular dystrophy, glycerol kinase deficiency, congenital adrenal hyperplasia and mental retardation (Jin et al, 2000). In addition, there are multiple reports in the literature of patients with non-syndromic mental retardation in association with microdeletions in Xp22.3 ] p22.1 (Wheway et al, 2003;Zhang et al, 2004;Tabolacci et al, 2006), thus the IL1RAPL1 gene is a strong candidate for X-linked non-syndromic mental retardation. DMD deficiency results in Duchenne muscular dystrophy (Koenig et al, 1987), which results in progressive deterioration of muscle tissues and resultant weakness but is also associated with neurological problems (Sekiguchi, 2005).…”

Construction of a high-density and high-resolution human chromosome X array for comparative genomic hybridization analysis

“…IL1RAPL2 is expressed strongly in the central nervous system not only in adulthood but also in the fetal period (Ferrante et al 2001), and partial or whole microdeletions of IL1RAPL1 in patients with XLMR have been reported (Carrié et al 1999). More recently, a truncating mutation of IL1RAPL1 was reported to be responsible for XLMR in a MRX21 family (Tabolacci et al 2006). However, no aberration of IL1RAPL2 at the nucleotide or chromosome level has been reported in any congenital anomalies, developmental disorders, or MR.…”