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.
| Lingua originale | English |
|---|---|
| pagine (da-a) | 482-487 |
| Numero di pagine | 6 |
| Rivista | AMERICAN JOURNAL OF MEDICAL GENETICS. PART A |
| Volume | 140 |
| DOI | |
| Stato di pubblicazione | Pubblicato - 2006 |
Keywords
- Grant number:GGP030202
- Grant sponsor: Conquer Fragile X Foundation
- Grantnumber: 2004.*Correspondence to: Giovanni Neri, M.D., Istituto di Genetica Medica,Universita`Cattolica, Largo F. Vito 1, 00168 Rome, Italy.E-mail: [email protected] 10.1002/ajmg.a.31107
- IL1RAPL1gene
- Kleefstra andHamel, 2005]. An updated list of these conditions canbe found in the XLMR Update Web site (http://xlmr.interfree.it/home.htm) and in the dedicatedpage at Greenwood Genetic Center (http://www.ggc.org/xlmr.htm). Some XLMR conditions, such asthe fragile X syndrome, are clinically recognizableand are considered specific (MRXS). On the otherhand, in many families the only manifestation sharedby patients is mental retardation. Such MRX pedi-grees are sometimes sufficiently large to allowlinkage analysis yielding a significant LOD score thatwill position the responsible gene in a given locationon the X chromosome. More than 80 MRX familieshavebeen reportedand mutationsin at least21XLMRgenes have been found in 24 of those families (http://xlmr.interfree.it/home.htm). Therefore, at least 50MRX pedigrees are still in search of a gene. TheMRX21 pedigree (Fig. 1) was reported by us in 1993[Kozak et al., 1993]. Linkage analysis had positionedthe responsible gene in a large interval between theXp telomere and
- MRX21
- X-linked mental retardation
- linkageanalysis
- stop mutationINTRODUCTIONX-linked mental retardation (XLMR) is a clinicallyvariable and genetically heterogeneous condition,due to mutations in more than 50 genes on the Xchromosome [Chiurazzi et al., 2004