Relevance to Autism

Several studies have found a genetic association between the RELN gene and autism. Positive associations have been found in the Italian and US populations, the Chinese Han population and Caucasian AGRE families (Persico et al., 2001; Serajee et al., 2006; Ashley-Koch et al., 2007; Li et al., 2008; Holt et al., 2010; Fu et al., 2013). However, several studies have also revealed lack of association between RELN and autism in a number of samples, including IMGSAC, CPEA, German and Chinese Han populations (Zhang et al., 2002; Bonora et al., 2003; Dutta et al., 2008; He et al., 2011). Variable expression data in ASD brain tissue has also been reported (Fatemi et al., 2005; Garbett et al., 2008). A de novo LoF variant in the RELN gene was identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760), while two de novo likely damaging missense variants have been observed in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (PMID 22542183, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified RELN as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760). Two additional de novo LoF variants and a likely damaging missense variant in RELN were identified in probands from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017 (PMID 28191889). Lammert et al., 2017 demonstrated that several ASD-associated missense variants in the RELN gene, including a de novo missense variant identified in a Simons Simplex Collection proband, resulted in reduced RELN protein secretion from transfected cells (PMID 28419454).

Molecular Function

This gene encodes a large secreted extracellular matrix protein thought to control cell-cell interactions critical for cell positioning and neuronal migration during brain development.

External Links

References

Model Summary

Homozygous reeler mice show decreased brain volume, increased volume of the ventricles and a severe defects in cerebellar foliation and reduced number of Purkinje cells. They also show morphological abnormalities in the hippocampus and disorganized amygdala, because of abnormal neuronal migration in these regions as well as in the cerebellum. These brain defects give rise to ataxia and severe problems with motor coordination.

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