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Molecular Autism
Published in: Molecular Autism 1/2010

Open Access 01-12-2010 | Research

Candidate gene study of HOXB1 in autism spectrum disorder

Authors: Lucia A Muscarella, Vito Guarnieri, Roberto Sacco, Paolo Curatolo, Barbara Manzi, Riccardo Alessandrelli, Grazia Giana, Roberto Militerni, Carmela Bravaccio, Carlo Lenti, Monica Saccani, Cindy Schneider, Raun Melmed, Leonardo D'Agruma, Antonio M Persico

Published in: Molecular Autism | Issue 1/2010

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Abstract

Background

HOXB1 plays a major role in brainstem morphogenesis and could partly determine the cranial circumference in conjunction with HOXA1. In our sample, HOXA1 alleles significantly influence head growth rates both in autistic patients and in population controls. An initial report, suggesting that HOXB1 could confer autism vulnerability in interaction with HOXA1, was not confirmed by five small association studies.

Methods

Our sample includes 269 autistic individuals, belonging to 219 simplex and 28 multiplex families. A mutational analysis of the two exons and flanking intronic sequences of the HOXB1 gene was carried out in 84 autistic patients by denaturing high performance liquid chromatography, followed by DNA sequencing. Identified rare variants were then searched by a restriction analysis in 236 autistic patients and 325-345 controls. Case-control and family-based association studies were performed on two common variants in 169 Italian patients versus 184 Italian controls and in 247 trios.

Results

We identified three common polymorphisms, rs72338773 [c.82insACAGCGCCC (INS/nINS)], rs12939811 [c.309A>T (Q103H)], and rs7207109 [c.450G>A (A150A)] and three rare variants, namely IVS1+63G>A, rs35115415 [c.702G>A (V234V)] and c.872_873delinsAA (S291N). SNPs rs72338773 and rs12939811 were not associated with autism, using either a case-control (alleles, exact P = 0.13) or a family-based design [transmission/disequilibrium test (TDT)χ2 = 1.774, P = 0.183]. The rare variants, all inherited from one of the parents, were present in two Italian and in two Caucasian-American families. Autistic probands in two families surprisingly inherited a distinct rare variant from each parent. The IVS1+63A allele was present in 3/690 control chromosomes, whereas rare alleles at rs35115415 and c.872_873delinsAA (S291N) were not found in 662 and 650 control chromosomes, respectively. The INS-T309 allele influenced head size, but its effect appears more modest and shows no interaction with HOXA1 alleles. The INS-T309 allele is also associated with more severe stereotypic behaviours, according to ADI-R scores (N = 60 patients, P < 0.01).

Conclusions

HOXB1 mutations do not represent a common cause of autism, nor do HOXB1 common variants play important roles in autism vulnerability. HOXB1 provides minor, albeit detectable contributions to head circumference in autistic patients, with HOXA1 displaying more prominent effects. HOXB1 variants may modulate the clinical phenotype, especially in the area of stereotypic behaviours.
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Metadata
Title
Candidate gene study of HOXB1 in autism spectrum disorder
Authors
Lucia A Muscarella
Vito Guarnieri
Roberto Sacco
Paolo Curatolo
Barbara Manzi
Riccardo Alessandrelli
Grazia Giana
Roberto Militerni
Carmela Bravaccio
Carlo Lenti
Monica Saccani
Cindy Schneider
Raun Melmed
Leonardo D'Agruma
Antonio M Persico
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Molecular Autism / Issue 1/2010
Electronic ISSN: 2040-2392
DOI
https://doi.org/10.1186/2040-2392-1-9

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