Genetic analyses of roundabout (ROBO) axon guidance receptors in autism.
Autism is a pervasive developmental disorder diagnosed in early childhood. Abnormalities of serotonergic neurotransmission have been reported in autism. Serotonin transporter (SERT) modulates serotonin levels, and is a major therapeutic target in autism. Factors that regulate SERT expression might be implicated in the pathophysiology of autism. One candidate SERT regulatory protein is the roundabout axon guidance molecule, ROBO. SerT expression in Drosophila is regulated by robo; it plays a vital role in mammalian neurodevelopment also. Here, we examined the associations of ROBO3 and ROBO4 with autism, in a trio association study using DNA from 252 families recruited to AGRE. Four SNPs of ROBO3 (rs3923890, P = 0.023; rs7925879, P = 0.017; rs4606490, P = 0.033; and rs3802905, P = 0.049) and a single SNP of ROBO4 (rs6590109, P = 0.009) showed associations with autism; the A/A genotype of rs3923890 showed lower ADI-R_A scores, which reflect social interaction. Significant haplotype associations were also observed for ROBO3 and ROBO4. We further compared the mRNA expressions of ROBO1, ROBO2, ROBO3, and ROBO4 in the lymphocytes of 19 drug-naïve autistic patients and 20 age- and sex-matched controls. Expressions of ROBO1 (P = 0.018) and ROBO2 (P = 0.023) were significantly reduced in the autistic group; the possibility of using the altered expressions of ROBO as peripheral markers for autism, may be explored. In conclusion, we suggest a possible role of ROBO in the pathogenesis of autism. Abnormalities of ROBO may lead to autism either by interfering with serotonergic system, or by disrupting neurodevelopment. To the best of our knowledge, this is the first report relating ROBO with autism.
Anitha
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Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Nakamura
Kazuhiko
K
Yamada
Kazuo
K
Suda
Shiro
S
Thanseem
Ismail
I
Tsujii
Masatsugu
M
Iwayama
Yoshimi
Y
Hattori
Eiji
E
Toyota
Tomoko
T
Miyachi
Taishi
T
Iwata
Yasuhide
Y
Suzuki
Katsuaki
K
Matsuzaki
Hideo
H
Kawai
Masayoshi
M
Sekine
Yoshimoto
Y
Tsuchiya
Kenji
K
Sugihara
Gen-Ichi
G
Ouchi
Yasuomi
Y
Sugiyama
Toshiro
T
Koizumi
Keita
K
Higashida
Haruhiro
H
Takei
Nori
N
Yoshikawa
Takeo
T
Mori
Norio
N
D000328:Adult; D044466:Asian People / Q000235:genetics; D001321:Autistic Disorder / Q000209:etiology / Q000235:genetics*; D016022:Case-Control Studies; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008214:Lymphocytes; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000032:analysis; D011971:Receptors, Immunologic / Q000235:genetics*; D000097905:Roundabout Proteins
D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D000097905:Roundabout Proteins