X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family

Abstract

A large French family including members affected by nonspecific X-linked mental retardation, with or without autism or pervasive developmental disorder in affected male patients, has been found to have a 2-base-pair deletion in the Neuroligin 4 gene (NLGN4) located at Xp22.33. This mutation leads to a premature stop codon in the middle of the sequence of the normal protein and is thought to suppress the transmembrane domain and sequences important for the dimerization of neuroligins that are required for proper cell-cell interaction through binding to beta-neurexins. As the neuroligins are mostly enriched at excitatory synapses, these results suggest that a defect in synaptogenesis may lead to deficits in cognitive development and communication processes. The fact that the deletion was present in both autistic and nonautistic mentally retarded males suggests that the NLGN4 gene is not only involved in autism, as previously described, but also in mental retardation, indicating that some types of autistic disorder and mental retardation may have common genetic origins.

Figure 1

Pedigree of family T118. The diagram shows the 13 males who were identified as having nonspecific MR (blackened squares), nonspecific MR with autism (diagonally striped squares), or pervasive developmental disorder (gray square). For eight subjects, diagnoses were made by direct examination or from medical records, and the five other males were institutionalized. A minus sign (−) above a symbol indicates that a blood sample was obtained for analysis.

Figure 2

Identification of the NLGN4 mutation in family T118. A, Schematic representation of the organization of the NLGN4 gene and representative NLGN4 sequence of normal, affected, and heterozygous subjects from family T118. PCR products of each coding exon (from 100 ng of DNA) were amplified (primers and PCR conditions available on request), purified through Sephadex G-50 columns, and analyzed by agarose-gel electrophoresis. The products were then sequenced using the ABI PRISM BigDye Terminator Sequencing Kit (PE Applied Biosystems) on an ABI PRISM 377 automated sequencer. The arrows mark the position of the NLGN4 mutation (cDNA nucleotide 1253). B, Sequence alignments between the normal and the predicted mutated NLGN4 proteins. The position of the mutation and the consequence on the amino acid sequence are indicated in red. C, Schematic representation of the NLGN4 protein with the predicted constitutive domains by homology with the other neuroligins. The region of dimerization is positioned at the base of the AchE domain and would be absent in the truncated NLGN4.