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PMID:19726642

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Citation

Zhang, C, Milunsky, JM, Newton, S, Ko, J, Zhao, G, Maher, TA, Tager-Flusberg, H, Bolliger, MF, Carter, AS, Boucard, AA, Powell, CM and Südhof, TC (2009) A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export. J. Neurosci. 29:10843-54

Abstract

Neuroligins (NLs) are postsynaptic cell-adhesion molecules essential for normal synapse function. Mutations in neuroligin-4 (NL4) (gene symbol: NLGN4) have been reported in some patients with autism spectrum disorder (ASD) and other neurodevelopmental impairments. However, the low frequency of NL4 mutations and the limited information about the affected patients and the functional consequences of their mutations cast doubt on the causal role of NL4 mutations in these disorders. Here, we describe two brothers with classical ASD who carry a single amino-acid substitution in NL4 (R87W). This substitution was absent from the brothers' asymptomatic parents, suggesting that it arose in the maternal germ line. R87 is conserved in all NL isoforms, and the R87W substitution is not observed in control individuals. At the protein level, the R87W substitution impaired glycosylation processing of NL4 expressed in HEK293 and COS cells, destabilized NL4, caused NL4 retention in the endoplasmic reticulum in non-neuronal cells and neurons, and blocked NL4 transport to the cell surface. As a result, the R87W substitution inactivated the synapse-formation activity of NL4 and abolished the functional effect of NL4 on synapse strength. Viewed together, these observations suggest that a point mutation in NL4 can cause ASD by a loss-of-function mechanism.

Links

PubMed PMC2777970 Online version:10.1523/JNEUROSCI.1248-09.2009

Keywords

Amino Acid Sequence; Amino Acid Substitution/genetics; Animals; Arginine/genetics; Autistic Disorder/genetics; Autistic Disorder/metabolism; COS Cells; Carrier Proteins/chemistry; Carrier Proteins/genetics; Carrier Proteins/metabolism; Cell Line; Cercopithecus aethiops; Child, Preschool; Endoplasmic Reticulum/genetics; Endoplasmic Reticulum/metabolism; Female; Humans; Male; Membrane Proteins/chemistry; Membrane Proteins/genetics; Membrane Proteins/metabolism; Mice; Molecular Sequence Data; Mutation, Missense/genetics; Protein Folding; Protein Transport/genetics; Tryptophan/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:NLGNX

located_in

GO:0009986: cell surface

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NLGNX

located_in

GO:0030425: dendrite

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NLGNX

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NLGNX

part_of

GO:0009986: cell surface

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NLGNX

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NLGNX

involved_in

GO:0035176: social behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NLGNX

part_of

GO:0030425: dendrite

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NLGNX

enables

GO:0042043: neurexin family protein binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NLGNX

involved_in

GO:0097105: presynaptic membrane assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NLGNX

involved_in

GO:0090394: negative regulation of excitatory postsynaptic potential

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NLGNX

involved_in

GO:0071625: vocalization behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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