MOLECULAR ANALYSIS OF THE L1CAM GENE IN PATIENTS WITH X-LINKED HYDROCEPHALUS DEMONSTRATES 8 NOVEL MUTATIONS AND SUGGESTS NON-ALLELIC HETEROGENEITY OF THE TRAIT

Eight novel mutations were identified in the gene encoding L1CAM, a ne ural cell adhesion protein, in patients/families with X-linked hydroce phalus (XHC) providing additional evidence for extreme allelic heterog eneity of the trait, The two nonsense mutations (Gln440Ter and Gln1042 Ter) result most likely in functional null-alleles and complete absenc e of L1CAM at the cell surface, The four missense mutations (Leu482Pro , Ser542Pro, Met741Thr, and Va1752Met) as well as delSer526 may consid erably alter the structure of L1CAM, Interestingly, a missense mutatio n in an XHC family predicting the Va1768Ile change in the second fibro nectin type III domain of L1CAM was found not only in the two affected cousins and their obligate carrier mothers but also in two unaffected male relatives of the patients, Several possible explanations of this finding are discussed; the most likely being that Val768Ile is a rare non-pathogenic variant, If this were indeed the case, our data sugges t that the XHC in this family is not due to a mutation of the L1CAM ge ne, i.e., that, in addition to the extreme allelic heterogeneity of XH C, a non-allelic form of genetic heterogeneity may also exist in this trait. (C) 1997 Wiley-Liss, Inc.