Association of Transcription Factor Gene LMX1B with Autism

Abstract

Multiple lines of evidence suggest a serotoninergic dysfunction in autism. The role of LMX1B in the development and maintenance of serotoninergic neurons is well known. In order to examine the role, if any, of LMX1B with autism pathophysiology, a trio-based SNP association study using 252 family samples from the AGRE was performed. Using pair-wise tagging method, 24 SNPs were selected from the HapMap data, based on their location and minor allele frequency. Two SNPs (rs10732392 and rs12336217) showed moderate association with autism with p values 0.018 and 0.022 respectively in transmission disequilibrium test. The haplotype AGCGTG also showed significant association (p = 0.008). Further, LMX1B mRNA expressions were studied in the postmortem brain tissues of autism subjects and healthy controls samples. LMX1B transcripts was found to be significantly lower in the anterior cingulate gyrus region of autism patients compared with controls (p = 0.049). Our study suggests a possible role of LMX1B in the pathophysiology of autism. Based on previous reports, it is likely to be mediated through a seretoninergic mechanism. This is the first report on the association of LMX1B with autism, though it should be viewed with some caution considering the modest associations we report.

The neuropathology of autism: A systematic review of post-mortem studies of autism and related disorders

“…Lower STX1A expression was also observed in the motor cortex of 7 cases (non-significant) (Nakamura et al, 2011). Similarly, the expression of LIM homeodomain transcription factor 1b (LMX1B), that plays a role in both the development and maintenance of serotoninergic neurons in the adult brain (Dolmazon et al, 2011, Song et al, 2011, was found to be significantly reduced in the anterior cingulate gyrus of autism patients (Thanseem et al, 2011). Moreover, Iwata et al (2014) identified Nethylmaleimide-sensitive factor (NSF) as a novel serotonin transporter-binding protein, and on examining mRNA expression of the serotonin transporter (SLC6A4) and NSF found no significant differences in SLC6A4 expression, although NSF expression showed a trend towards a reduction (Iwata et al, 2014).…”

Cell fate determination, neuronal maintenance and disease state: The emerging role of transcription factors Lmx1a and Lmx1b

“…The role of LMX1B in autism pathophysiology has also been assessed through genetic polymorphism and postmortem autistic brain analysis. A family trio‐based study found two SNPs in LMX1B locus associated with autism [104]. LMX1B mRNA expression was also found to be significantly lower in the anterior cingulate gyrus region of autism patients compared with controls [104].…”

Dysregulation of WTI (−KTS) is Associated with the Kidney-Specific Effects of the LMX1B R246Q Mutation

“…Glaucoma is one of the manifestation of classical NPS, but we are not aware of the report of an association of autism with LMX1B mutation in NPS. An association between autism and common variants in LMX1B has been reported in a small cohort of patients30. It is therefore likely that the finding of autism in our patients may represent effects of other variants in LMX1B and other modifier genes.…”