NEW DOMAINS OF NEURAL CELL-ADHESION MOLECULE L1 IMPLICATED IN X-LINKED HYDROCEPHALUS AND MASA SYNDROME

The neural cell-adhesion molecule L1 is involved in intercellular reco gnition and neuronal migration in the CNS. Recently, we have shown tha t mutations in the gene encoding L1 are responsible for three related disorders; X-linked hydrocephalus, MASA (mental retardation, aphasia, shuffling gait, and adducted thumbs) syndrome, and spastic paraplegia type I (SPG1). These three disorders represent a clinical spectrum tha t varies not only between families but sometimes also within families. To date, 14 independent L1 mutations have been reported and shown to be disease causing. Here we report nine novel L1 mutations in X-linked hydrocephalus and MASA-syndrome families, including the first example s of mutations affecting the fibronectin type III domains of the molec ule. They are discussed in relation both to phenotypes and to the insi ghts that they provide into L1 function.