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CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila


Zweier, C; de Jong, E K; Zweier, M; Oricco, A; Ousager, L B; Collins, A L; Bijlsma, E K; Oortveld, M A V; Ekici, A B; Reis, A; Schenck, A; 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. American Journal of Human Genetics, 85(5):655-666.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Genetics
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Date:13 November 2009
Deposited On:23 Feb 2010 08:50
Last Modified:05 Apr 2016 13:58
Publisher:Elsevier
ISSN:0002-9297
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.ajhg.2009.10.004
PubMed ID:19896112
Permanent URL: https://doi.org/10.5167/uzh-31597

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