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.

Mutations in the ribosomal protein gene RPL10 suggest a novel modulating disease mechanism for autism

“…Mutations in the neuroligin genes NLGN4 and NLGN3, also located on the X chromosome, have been detected recently in a few cases of autistic disorder or XLMR with and without autistic disorder, respectively. 47,48 It remains to be elucidated whether such rare cases of autism have common genetic causes with some forms of mental retardation. (iv) Interneurons in the CA3 region of the hippocampal complex play a significant role in controlling hippocampal neuronal excitability by interaction 4 The neurotransmitter serotonin is involved in neuronal excitability of interneurons in hippocampus with influence on dendritic atrophy.…”

The genetics of autistic disorders and its clinical relevance: a review of the literature

“…[251][252][253] One study 254 detected several other variants in NLGN3 and NLGN4X; however, only nominal significance for association with AD was found. As the NLGN4X nt1253del(AG) frameshift mutation found in one study 249 co-segregated with unspecific mental retardation and AD in one large family, it is likely that NLGN4X mutations might be rare single gene disorders causing AD and unspecific mental retardation. Owing to the rare occurrence of the observed variants in larger samples of individuals with AD, however, it is unlikely that the NLGN3 and NLGN4X genes play an important role in idiopathic autism.…”

Not all neuroligin 3 and 4X missense variants lead to significant functional inactivation

“…Accumulating evidence suggests involvement of the neuroligin family in autism and other neuropsychiatric disorders (Jamain et al., 2003; Laumonnier et al., 2004; Lawson‐Yuen, Saldivar, Sommer, & Picker, 2008; Philippe et al., 1999; Sindi, Tannenberg, & Dodd, 2014; Thomas et al., 1999). In 2003, a mutation in neuroligin 3 ( NLGN3 ; p.R451C) and a mutation in neuroligin 4X ( NLGN4X ; p.D396 fs) were reported in two unrelated Swedish autism families (Jamain et al., 2003).…”

“…In 2003, a mutation in neuroligin 3 ( NLGN3 ; p.R451C) and a mutation in neuroligin 4X ( NLGN4X ; p.D396 fs) were reported in two unrelated Swedish autism families (Jamain et al., 2003). Since then, several other mutations in the NLGN3 , NLGN4X , and NLGN4Y genes have been reported to be related to autism (Chih, Afridi, Clark, & Scheiffele, 2004; Daoud et al., 2009; Kuroda et al., 2014; Laumonnier et al., 2004; Lawson‐Yuen et al., 2008; Talebizadeh et al., 2006; Yan et al., 2005, 2008). In vitro and in vivo experiments have indicated that the autism‐related neuroligin mutations may affect synapse maturation and function.…”