全周 (9AM - 6PM)

我们和你在一起

Extra info thumb
NEUROLIGIN 4; NLGN4

NEUROLIGIN 4; NLGN4

Alternative titles; symbolsNLGN4XNL4KIAA1260HGNC Approved Gene Symbol: NLGN4XCytogenetic location: Xp22.32-p22.31 Genomic coordinates (GRCh38): X:5,890,041-6...

Alternative titles; symbols

  • NLGN4X
  • NL4
  • KIAA1260

HGNC Approved Gene Symbol: NLGN4X

Cytogenetic location: Xp22.32-p22.31 Genomic coordinates (GRCh38): X:5,890,041-6,228,877 (from NCBI)

▼ Cloning and Expression
By sequencing clones obtained from a size-fractionated adult brain cDNA library, Nagase et al. (1999) cloned NLGN4, which they designated KIAA1260. The deduced 817-amino acid protein shares 75% identity with NLGN1 (600568) and 71% identity with rat Nlgn3 (300336). RT-PCR ELISA detected high expression of NLGN4 in whole brain and in all individual brain regions examined. High expression was also found in ovary, and lower expression was found in all other tissues tested except pancreas.

By database analysis, Jamain et al. (2008) identified human NLGN4, which encodes an 873-amino acid protein containing a signal peptide, esterase domain, transmembrane domain, and PDZ domain-binding motif. They cloned mouse Nlgn4 and determined that the 945-amino acid mouse protein shares 57% identity with human NLGN4. Murine Nlgn4 was expressed in mouse thymus and brain, with highest expression in hippocampus, cortex, and septum, and lowest expression in brainstem and cerebellum. Nlgn4 expression increased from low levels during embryonic and early postnatal phases to reach a plateau at 3 weeks after birth, consistent with synaptic expression. Subcellular fractionation of brain homogenates showed enrichment of Nlgn4 in synaptic membrane fractions.

Bolliger et al. (2008) cloned mouse Nl4 and found that it diverges dramatically from orthologs in other species. They determined that mouse Nl4 contains a high density of repetitive sequences and exhibits significant sequence variation among mouse strains.

▼ Gene Function
Bolliger et al. (2008) found that, despite the sequence differences between mouse Nl4 and other neuroligins, Nl4 bound to neurexins and localized to dendritic spines when overexpressed.

Using predominantly human and rodent constructs, Graf et al. (2004) found that neurexin-1 (NRXN1)-beta (600565) expressed in nonneuronal cells clustered the postsynaptic proteins gephyrin (GPHN; 603930) and PSD95 (DLG4; 602887), neurotransmitter receptors, and all 4 neuroligins in cocultured rodent hippocampal neurons. The isolated LNS domain of NRXN1-beta was sufficient for this synaptogenic activity when expressed in cells or immobilized on beads. Neuroligin aggregation alone was synaptogenic, but it showed some specificity: neuroligins-1, -3 and -4 linked only to glutamatergic postsynaptic proteins, but neuroligin-2 (NLGN2; 606479) linked to both glutamatergic and GABAergic postsynaptic proteins.

▼ Mapping
By radiation hybrid analysis, Nagase et al. (1999) mapped the NLGN4 gene to the X chromosome. Bolliger et al. (2008) determined that the mouse Nlgn4 gene maps to an autosome.

▼ Molecular Genetics
In 2 brothers, 1 with X-linked autism (AUTSX2; 300495) and 1 with X-linked Asperger syndrome (ASPGX2; 300497), Jamain et al. (2003) identified a mutation in the NLGN4 gene (300427.0001).

▼ Animal Model
Jamain et al. (2008) found that Ngln4-null mice showed selective deficits in reciprocal social interaction and communication reminiscent of autistic disorders in humans. Behavioral changes were not due to sensory, locomotor, or memory deficits, which were normal in the mutant mice. Mutant mice showed small but significant decreases in brain gray matter compared to wildtype mice.

▼ ALLELIC VARIANTS ( 3 Selected Examples):

.0001 AUTISM, SUSCEPTIBILITY TO, X-LINKED 2
ASPERGER SYNDROME, SUSCEPTIBILITY TO, X-LINKED 2, INCLUDED
NLGN4, 1-BP INS, 1186T
In a Swedish family in which 1 brother had X-linked autism (300495) and another had X-linked Asperger syndrome (300497), Jamain et al. (2003) identified a frameshift mutation (1186T) in the NLGN4 gene, resulting in a stop codon at position 396 and premature termination of the protein before the transmembrane domain. The mutation was present in the mother and absent in an unaffected brother and 350 controls. Jamain et al. (2003) suggested that the mutation may modify the binding of the neuroligin protein to its presynaptic partners, neurexins (see 600565), thus interrupting essential synaptic function.

Chih et al. (2004) demonstrated that the mutation resulting in premature termination at aspartate-396 of NLGN4 resulted in intracellular retention of the mutant proteins. Overexpression of wildtype NLGN protein in hippocampal neurons stimulated the formation of presynaptic terminals, whereas the disease-associated mutation resulted in a loss of this synaptic function. The authors hypothesized that the neurodevelopmental defects in autism spectrum disorders and mental retardation may be due to impaired function of a synaptic cell adhesion molecule.

.0002 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED
AUTISM, SUSCEPTIBILITY TO, X-LINKED 2, INCLUDED
NLGN4, 2-BP DEL, 1253AG
In all affected members of a large French family with X-linked intellectual developmental disorder, with or without autism or pervasive developmental disorder (see 300495), Laumonnier et al. (2004) identified a 2-bp deletion, 1253delAG, in the fifth exon of the NLGN4 gene. The deletion caused a frameshift and a premature stop codon, and was predicted to result in a protein of 429 amino acids, a truncation of approximately 50%. Healthy males in the family did not have the deletion, and obligate carrier females were heterozygous for the mutation. Laumonnier et al. (2004) noted that mutations in the NLGN4 gene are involved in a wide spectrum of phenotypes.

.0003 AUTISM, SUSCEPTIBILITY TO, X-LINKED 2
MENTAL RETARDATION, X-LINKED, INCLUDED
NLGN4, 757-KB DEL
In a boy with autism and mental retardation (300495) as well as a motor tic, Lawson-Yuen et al. (2008) identified a hemizygous deletion in the NLGN4 gene encompassing exons 4, 5, and 6. The 757-kb deletion was predicted to result in a significantly truncated protein. The patient's 9-year-old brother, who carried diagnoses of Tourette syndrome (see 309840) and attention deficit-hyperactivity disorder with mild cognitive deficits, also carried the deletion. The mother, who was a carrier, had a learning disability, depression, and anxiety. Lawson-Yuen et al. (2008) concluded that NLGN4 mutations can be associated with a wide spectrum of neuropsychiatric disorders.

Tags: XP22.31, Xp22.32