Gene Defect Tied to Autism in Small Number of Cases - NLGN4 glitch in 3% of 148 autistics - neuroligin 4

[Guest guest]

Gene Defect Tied to Autism in Small Number of Cases

By H. Maugh II

LATimes Staff Writer

January 1, 2005

http://www.latimes.com/news/science/la-sci-autism1jan01,1,4146147.story

City of Hope researchers have identified a gene defect that may cause

autism in a small percentage of cases.

The discovery provides new insight into how the debilitating disorder,

which affects as many as one in 500 children, develops.

Dr. Steve Sommer, a molecular geneticist at the medical center in

Duarte, reported in the current issue of the journal Molecular

Psychiatry that 3% of 148 unrelated autism patients his team studied had

a defect in a gene called neuroligin 4, or NLGN4. The defective gene was

not found in any of 336 healthy patients.

NLGN4 plays a role in forming certain types of synapses, which are the

communication connections between nerve cells. Higher thought processes

depend on the formation of adequate numbers of synapses. An inadequate

number may lead to the symptoms of autism, which include poor language

skills and an inability to handle social relations.

The new results complement two recent French studies. In one, French

researchers found a truncated form of the protein produced by NLGN4 in a

boy with autism. In the second study, a team found a mutated form of the

gene in a family in which several members had autism.

The research " provides rather compelling evidence that defective NLGN4

genes predispose individuals to autism, " Sommer said.

1: Mol Psychiatry. 2004 Dec 28; [Epub ahead of print]

Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric

patients.

Yan J, Oliveira G, Coutinho A, Yang C, Feng J, Katz C, Sram J, Bockholt A,

IR, Craddock N, Cook EH, Vicente A, Sommer SS.

1Department of Molecular Genetics, City of Hope National Medical Center, CA,

USA.

PMID: 15622415 [PubMed - as supplied by publisher]

2: Cell. 2004 Dec 29;119(7):1013-26.

Neurexins Induce Differentiation of GABA and Glutamate Postsynaptic

Specializations via Neuroligins.

Graf ER, Zhang X, Jin SX, Linhoff MW, Craig AM.

Department of Anatomy and Neurobiology, Washington University School of

Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110 USA.

Formation of synaptic connections requires alignment of neurotransmitter

receptors on postsynaptic dendrites opposite matching transmitter release sites

on presynaptic axons. beta-neurexins and neuroligins form a trans-synaptic link

at glutamate synapses. We show here that neurexin alone is sufficient to induce

glutamate postsynaptic differentiation in contacting dendrites. Surprisingly,

neurexin also induces GABA postsynaptic differentiation. Conversely, neuroligins

induce presynaptic differentiation in both glutamate and GABA axons. Whereas

neuroligins-1, -3, and -4 localize to glutamate postsynaptic sites, neuroligin-2

localizes primarily to GABA synapses. Direct aggregation of neuroligins reveals

a linkage of neuroligin-2 to GABA and glutamate postsynaptic proteins, but the

other neuroligins only to glutamate postsynaptic proteins. Furthermore,

mislocalized expression of neuroligin-2 disperses postsynaptic proteins and

disrupts synaptic transmission. Our findings indicate that the

neurexin-neuroligin link is a core component mediating both GABAergic and

glutamatergic synaptogenesis, and differences in isoform localization and

binding affinities may contribute to appropriate differentiation and

specificity.

PMID: 15620359 [PubMed - in process]

3: Mol Cell Neurosci. 2004 Dec;27(4):497-508.

Synaptic scaffolding molecule is involved in the synaptic clustering of

neuroligin.

Iida J, Hirabayashi S, Sato Y, Hata Y.

Department of Medical Biochemistry, Graduate School of Medicine, Tokyo Medical

and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan.

S-SCAM has a similar molecular organization to PSD-95. Both of them interact

with a cell adhesion molecule, neuroligin. We previously reported that

beta-catenin binds S-SCAM and recruits it to synapses. We have here examined

using rat primary cultured neurons whether neuroligin recruits S-SCAM to

synapses or S-SCAM determines the localization of neuroligin. Overexpressed

neuroligin formed larger clusters under co-expression of S-SCAM but not of

PSD-95. Overexpressed neuroligin blocked synaptic accumulation of PSD-95 but not

of S-SCAM. S-SCAM mutant containing the neuroligin-binding region interfered

with synaptic accumulation of neuroligin and PSD-95, whereas the similar mutant

of PSD-95 had no effect. Biochemical studies revealed that neuroligin forms a

ternary complex with S-SCAM and PSD-95 through manifold interactions. These

findings imply that S-SCAM is tethered by beta-catenin to synapses and induces

synaptic accumulation of neuroligin, which subsequently recruits PSD-95 to

synapses.

PMID: 15555927 [PubMed - in process]

4: Am J Med Genet B Neuropsychiatr Genet. 2004 Jun 28;132B(1):74-75 [Epub ahead

of print]

NLGN3/NLGN4 gene mutations are not responsible for autism in the Quebec

population.

Gauthier J, Bonnel A, St-Onge J, Karemera L, t S, Mottron L, Fombonne E,

Joober R, Rouleau GA.

Research Institute of the McGill University Health Center, Cedar Ave, Montreal,

Canada.

Jamain [2003: Nat Genet 34:27-29] recently reported mutations in two neuroligin

genes in sib-pairs affected with autism. In order to confirm these causative

mutations in our autistic population and to determine their frequency we

screened 96 individuals affected with autism. We found no mutations in these

X-linked genes. These results indicate that mutations in NLGN3 and NLGN4 genes

are responsible for at most a small fraction of autism cases and additional

screenings in other autistic populations are needed to better determine the

frequency with which mutations in NLGN3 and NLGN4 occur in autism. © 2004

Wiley-Liss, Inc.

PMID: 15389766 [PubMed - as supplied by publisher]

5: Am J Med Genet. 2004 Aug 15;129B(1):82-4.

Mutation screening of X-chromosomal neuroligin genes: no mutations in 196 autism

probands.

JB, Kolozsvari D, WS, Bolton PF, Gurling HM, Scherer SW.

Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, ON,

Canada. john_vincent@...

Autism, a childhood neuropsychiatric disorder with a strong genetic component,

is currently the focus of considerable attention within the field of human

genetics as well many other medical-related disciplines. A recent study has

implicated two X-chromosomal neuroligin genes, NLGN3 and NLGN4, as having an

etiological role in autism, having identified a frameshift mutation in one gene

and a substitution mutation in the other, segregating in multiplex autism

spectrum families (Jamain et al. [2003: Nat Genet 34:27-29]). The function of

neuroligin as a trigger for synapse formation would suggest that such mutations

would likely result in some form of pathological manifestation. Our own study,

screening a larger sample of 196 autism probands, failed to identify any

mutations that would affect the coding regions of these genes. Our findings

suggest that mutations in these two genes are infrequent in autism. Copyright

2004 Wiley-Liss, Inc.

PMID: 15274046 [PubMed - in process]

6: J Neurochem. 2004 Jul;90(2):332-9.

Synaptic scaffolding molecule interacts with axin.

Hirabayashi S, Nishimura W, Iida J, Kansaku A, Kishida S, Kikuchi A, Tanaka N,

Hata Y.

Department of Medical Biochemistry, Graduate School of Medicine, Tokyo Medical

and Dental University, Tokyo, Japan.

Synaptic scaffolding molecule (S-SCAM) is a synaptic protein that consists of

PDZ domains, a guanylate kinase domain, and WW domains. It interacts with

N-methyl-d-aspartate receptor subunits, neuroligin, and beta-catenin. Here, we

identified Axin as a novel binding partner of S-SCAM. Axin was

co-immunoprecipitated with S-SCAM from rat brain, detected in the post-synaptic

density fraction in rat brain subcellular fractionation, and partially

co-localized with S-SCAM in neurons. The guanylate kinase domain of S-SCAM

directly bound to the GSK3beta-binding region of Axin. S-SCAM formed a complex

with beta-catenin and Axin, but competed with GSK3beta for Axin-binding.

Thereby, S-SCAM inhibited the Axin-mediated phosphorylation of beta-catenin by

GSK3beta.

PMID: 15228590 [PubMed - indexed for MEDLINE]

7: Hum Mol Genet. 2004 Jul 15;13(14):1471-7. Epub 2004 May 18.

Disorder-associated mutations lead to functional inactivation of neuroligins.

Chih B, Afridi SK, L, Scheiffele P.

Department of Physiology and Cellular Biophysics, Center for Neurobiology and

Behavior, Columbia University, New York, NY 10032, USA.

Autism is a neuro-developmental syndrome that affects 0.1-0.5% of the

population. It has been proposed that alterations in neuronal circuitry and/or

neuronal signaling are responsible for the behavioral and cognitive aberrations

in autism patients. However, the cellular basis of such alterations is unknown.

Recently, point mutations in a family of neuronal cell adhesion molecules called

neuroligins have been linked to autism-spectrum disorders and mental

retardation. We investigated the consequences of these disease-associated

mutations on neuroligin function. We demonstrate that the point mutation at

arginine 451 and a nonsense mutation at aspartate 396 of neuroligin-3 and -4

(NL3 and NL4), respectively, result in intracellular retention of the mutant

proteins. Over-expression of wild-type NL3 and NL4 proteins in hippocampal

neurons stimulates the formation of presynaptic terminals, whereas the

disease-associated mutations result in a loss of this synaptic function. Our

findings suggest that the previously identified mutations in neuroligin genes

are likely to be relevant for the neuro-developmental defects in autism-spectrum

disorders and mental retardation since they impair the function of a synaptic

cell adhesion molecule.

PMID: 15150161 [PubMed - in process]

8: Am J Hum Genet. 2004 Mar;74(3):552-7. Epub 2004 Feb 12.

X-linked mental retardation and autism are associated with a mutation in the

NLGN4 gene, a member of the neuroligin family.

Laumonnier F, Bonnet-Brilhault F, Gomot M, Blanc R, A, Moizard MP, Raynaud

M, Ronce N, Lemonnier E, Calvas P, Laudier B, Chelly J, Fryns JP, Ropers HH,

Hamel BC, Andres C, Barthelemy C, Moraine C, Briault S.

INSERM U619-Genetique de l'Autisme et de la Deficience Mentale, CHU Bretonneau,

Tours, France.

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.

PMID: 14963808 [PubMed - indexed for MEDLINE]

9: Science. 2003 Oct 31;302(5646):826-30.

Postnatal neurodevelopmental disorders: meeting at the synapse?

Zoghbi HY.

Departments of Pediatrics, Neurology, and Molecular and Human Genetics, Division

of Neuroscience, and Medical Institute, Baylor College of

Medicine, Houston, TX 77030, USA. hzoghbi@...

We often think of neurodevelopmental disorders as beginning before birth, and

many certainly do. A handful, however, strike many months after birth, following

a period of apparently normal growth and development. Autism and Rett syndrome

are two such disorders, and here I consider some of their similarities at the

phenotypic and pathogenic levels. I propose that both disorders result from

disruption of postnatal or experience-dependent synaptic plasticity.

PMID: 14593168 [PubMed - indexed for MEDLINE]

*

The material in this post is distributed without profit to those

who have expressed a prior interest in receiving the included

information for research and educational purposes.

For more information go to:

http://www4.law.cornell.edu/uscode/17/107.html

<http://oregon.uoregon.edu/%7Ecsundt/documents.htm>

http://oregon.uoregon.edu/~csundt/documents.htm

<http://oregon.uoregon.edu/%7Ecsundt/documents.htm>

If you wish to use copyrighted material from this email for

purposes that go beyond 'fair use', you must obtain permission

from the copyright owner.