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PMID:19896112

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Citation

Zweier, C, de Jong, EK, Zweier, M, Orrico, A, Ousager, LB, Collins, AL, Bijlsma, EK, Oortveld, MA, Ekici, AB, Reis, A, Schenck, A and Rauch, A (2009) CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. Am. J. Hum. Genet. 85:655-66

Abstract

Heterozygous copy-number variants and SNPs of CNTNAP2 and NRXN1, two distantly related members of the neurexin superfamily, have been repeatedly associated with a wide spectrum of neuropsychiatric disorders, such as developmental language disorders, autism spectrum disorders, epilepsy, and schizophrenia. We now identified homozygous and compound-heterozygous deletions and mutations via molecular karyotyping and mutational screening in CNTNAP2 and NRXN1 in four patients with severe mental retardation (MR) and variable features, such as autistic behavior, epilepsy, and breathing anomalies, phenotypically overlapping with Pitt-Hopkins syndrome. With a frequency of at least 1% in our cohort of 179 patients, recessive defects in CNTNAP2 appear to significantly contribute to severe MR. Whereas the established synaptic role of NRXN1 suggests that synaptic defects contribute to the associated neuropsychiatric disorders and to severe MR as reported here, evidence for a synaptic role of the CNTNAP2-encoded protein CASPR2 has so far been lacking. Using Drosophila as a model, we now show that, as known for fly Nrx-I, the CASPR2 ortholog Nrx-IV might also localize to synapses. Overexpression of either protein can reorganize synaptic morphology and induce increased density of active zones, the synaptic domains of neurotransmitter release. Moreover, both Nrx-I and Nrx-IV determine the level of the presynaptic active-zone protein bruchpilot, indicating a possible common molecular mechanism in Nrx-I and Nrx-IV mutant conditions. We therefore propose that an analogous shared synaptic mechanism contributes to the similar clinical phenotypes resulting from defects in human NRXN1 and CNTNAP2.

Links

PubMed PMC2775834 Online version:10.1016/j.ajhg.2009.10.004

Keywords

Adolescent; Adult; Animals; Cell Adhesion Molecules, Neuronal; Child; Cohort Studies; Drosophila/genetics; Drosophila Proteins/genetics; Female; Gene Dosage; Genes, Recessive; Humans; Intellectual Disability/genetics; Male; Membrane Proteins/genetics; Mutation; Nerve Tissue Proteins/genetics; Pedigree; Polymorphism, Single Nucleotide; Synapses/genetics

Significance

Annotations

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

DROME:NRX4

located_in

GO:0045202: synapse

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:NRX4

located_in

GO:0048786: presynaptic active zone

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:NRX4

involved_in

GO:0072553: terminal button organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:NRX4

involved_in

GO:0097105: presynaptic membrane assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NRX1A

involved_in

GO:0030534: adult behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NRX1A

involved_in

GO:0007612: learning

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NRX1A

NOT|involved_in

GO:0050885: neuromuscular process controlling balance

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NRX1A

involved_in

GO:0071625: vocalization behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NRX1A

involved_in

GO:0042297: vocal learning

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NRX1A

involved_in

GO:0035176: social behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q9VCZ9

involved_in

GO:0072553: terminal button organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q9VCZ9

involved_in

GO:0097105: presynaptic membrane assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CNTP2

involved_in

GO:0042297: vocal learning

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CNTP2

involved_in

GO:0035176: social behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CNTP2

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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