Disruption of neurexin 1 associated with autism spectrum disorder.
Autism is a neurodevelopmental disorder of complex etiology in which genetic factors play a major role. We have implicated the neurexin 1 (NRXN1) gene in two independent subjects who display an autism spectrum disorder (ASD) in association with a balanced chromosomal abnormality involving 2p16.3. In the first, with karyotype 46,XX,ins(16;2)(q22.1;p16.1p16.3)pat, NRXN1 is directly disrupted within intron 5. Importantly, the father possesses the same chromosomal abnormality in the absence of ASD, indicating that the interruption of alpha-NRXN1 is not fully penetrant and must interact with other factors to produce ASD. The breakpoint in the second subject, with 46,XY,t(1;2)(q31.3;p16.3)dn, occurs approximately 750 kb 5' to NRXN1 within a 2.6 Mb genomic segment that harbors no currently annotated genes. A scan of the NRXN1 coding sequence in a cohort of ASD subjects, relative to non-ASD controls, revealed that amino acid alterations in neurexin 1 are not present at high frequency in ASD. However, a number of rare sequence variants in the coding region, including two missense changes in conserved residues of the alpha-neurexin 1 leader sequence and of an epidermal growth factor (EGF)-like domain, respectively, suggest that even subtle changes in NRXN1 might contribute to susceptibility to ASD.
Kim
Hyung-Goo
HG
Molecular Neurogenetics Unit, Center for Human Genetic Research and Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Kishikawa
Shotaro
S
Higgins
Anne W
AW
Seong
Ihn-Sik
IS
Donovan
Diana J
DJ
Shen
Yiping
Y
Lally
Eric
E
Weiss
Lauren A
LA
Najm
Juliane
J
Kutsche
Kerstin
K
Descartes
Maria
M
Holt
Lynn
L
Braddock
Stephen
S
Troxell
Robin
R
Kaplan
Lee
L
Volkmar
Fred
F
Klin
Ami
A
Tsatsanis
Katherine
K
Harris
David J
DJ
Noens
Ilse
I
Pauls
David L
DL
Daly
Mark J
MJ
MacDonald
Marcy E
ME
Morton
Cynthia C
CC
Quade
Bradley J
BJ
Gusella
James F
JF
D001321:Autistic Disorder / Q000235:genetics*; D002869:Chromosome Aberrations; D002889:Chromosomes, Human, Pair 2; D020022:Genetic Predisposition to Disease; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D020125:Mutation, Missense; D009479:Neuropeptides / Q000737:chemistry / Q000235:genetics*; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA
D006023:Glycoproteins; D009479:Neuropeptides; C112162:neurexophilin