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RELN Mutations in Autism Spectrum Disorder.

Lammert DB, Howell BW - Front Cell Neurosci (2016)

Bottom Line: Several lines of evidence from multiple studies now implicate heterozygous mutations in RELN in autism spectrum disorders (ASD).The RELN mutations that are most clearly consequential are those that are predicted to inactivate the signaling function of the encoded protein and those that fall in a highly conserved RXR motif found at the core of the 16 Reelin subrepeats.Despite the growing evidence of RELN dysfunction in ASD, it appears that these mutations in isolation are insufficient and that secondary genetic or environmental factors are likely required for a diagnosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience and Physiology, SUNY Upstate Medical School Syracuse, NY, USA.

ABSTRACT
RELN encodes a large, secreted glycoprotein integral to proper neuronal positioning during development and regulation of synaptic function postnatally. Rare, homozygous, mutations lead to lissencephaly with cerebellar hypoplasia (LCH), accompanied by developmental delay and epilepsy. Until recently, little was known about the frequency or consequences of heterozygous mutations. Several lines of evidence from multiple studies now implicate heterozygous mutations in RELN in autism spectrum disorders (ASD). RELN maps to the AUTS1 locus on 7q22, and at this time over 40 distinct mutations have been identified that would alter the protein sequence, four of which are de novo. The RELN mutations that are most clearly consequential are those that are predicted to inactivate the signaling function of the encoded protein and those that fall in a highly conserved RXR motif found at the core of the 16 Reelin subrepeats. Despite the growing evidence of RELN dysfunction in ASD, it appears that these mutations in isolation are insufficient and that secondary genetic or environmental factors are likely required for a diagnosis.

No MeSH data available.


Related in: MedlinePlus

The structure of Reelin is diagrammed with conserved domain boundaries mapped (NCBI Conserved Domain Database). (A) Missense, nonsense, and frameshift mutations that are absent in controls and thus more likely to contribute to ASD are indicated (*Bonora et al., 2003; @Neale et al., 2012; +Koshimizu et al., 2013; #De Rubeis et al., 2014; ∧Iossifov et al., 2014; ~Yuen et al., 2015; =Zhang et al., 2015). Specifically, mutations identified by Bonora et al. (2003) and De Rubeis et al. (2014) as occurring in isolated controls from case-control studies, even if they overlap with mutations identified in other studies, are not pictured. This process did not remove any RXR mutations identified in ASD probands; however, three RXR mutations were identified in controls: R1198H, R2104H, and R2292H. Missense mutations are colored based on PolyPhen2 predictions (green, benign; orange, possibly damaging; red, probably damaging). Nonsense and frameshift mutations are indicated in black. (B) Clustal Omega alignment of the sub-repeat domains is annotated with the corresponding missense mutations from (A). The RXR consensus sequence is indicated below the aligned repeat sequence. Note: corrections to annotations for missense mutations from supplementary file S4 of De Rubeis et al. (2014) are as follows: R3439Q to R3441Q, G254V to G2737V, R156H to R2639H.
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Figure 2: The structure of Reelin is diagrammed with conserved domain boundaries mapped (NCBI Conserved Domain Database). (A) Missense, nonsense, and frameshift mutations that are absent in controls and thus more likely to contribute to ASD are indicated (*Bonora et al., 2003; @Neale et al., 2012; +Koshimizu et al., 2013; #De Rubeis et al., 2014; ∧Iossifov et al., 2014; ~Yuen et al., 2015; =Zhang et al., 2015). Specifically, mutations identified by Bonora et al. (2003) and De Rubeis et al. (2014) as occurring in isolated controls from case-control studies, even if they overlap with mutations identified in other studies, are not pictured. This process did not remove any RXR mutations identified in ASD probands; however, three RXR mutations were identified in controls: R1198H, R2104H, and R2292H. Missense mutations are colored based on PolyPhen2 predictions (green, benign; orange, possibly damaging; red, probably damaging). Nonsense and frameshift mutations are indicated in black. (B) Clustal Omega alignment of the sub-repeat domains is annotated with the corresponding missense mutations from (A). The RXR consensus sequence is indicated below the aligned repeat sequence. Note: corrections to annotations for missense mutations from supplementary file S4 of De Rubeis et al. (2014) are as follows: R3439Q to R3441Q, G254V to G2737V, R156H to R2639H.

Mentions: Large and small scale WES studies of ASD individuals consistently identify missense and nonsense mutations in RELN, leading researchers to emphasize its importance in ASD (De Rubeis et al., 2014). There are currently over 40 unique RELN variants identified in ASD probands that are absent in controls (Bonora et al., 2003; Neale et al., 2012; Koshimizu et al., 2013; De Rubeis et al., 2014; Iossifov et al., 2014; Yuen et al., 2015; Zhang et al., 2015; Figure 2). These mutations have not been functionally characterized; however, strong predictions regarding their consequences can be deduced based on Reelin structure and function.


RELN Mutations in Autism Spectrum Disorder.

Lammert DB, Howell BW - Front Cell Neurosci (2016)

The structure of Reelin is diagrammed with conserved domain boundaries mapped (NCBI Conserved Domain Database). (A) Missense, nonsense, and frameshift mutations that are absent in controls and thus more likely to contribute to ASD are indicated (*Bonora et al., 2003; @Neale et al., 2012; +Koshimizu et al., 2013; #De Rubeis et al., 2014; ∧Iossifov et al., 2014; ~Yuen et al., 2015; =Zhang et al., 2015). Specifically, mutations identified by Bonora et al. (2003) and De Rubeis et al. (2014) as occurring in isolated controls from case-control studies, even if they overlap with mutations identified in other studies, are not pictured. This process did not remove any RXR mutations identified in ASD probands; however, three RXR mutations were identified in controls: R1198H, R2104H, and R2292H. Missense mutations are colored based on PolyPhen2 predictions (green, benign; orange, possibly damaging; red, probably damaging). Nonsense and frameshift mutations are indicated in black. (B) Clustal Omega alignment of the sub-repeat domains is annotated with the corresponding missense mutations from (A). The RXR consensus sequence is indicated below the aligned repeat sequence. Note: corrections to annotations for missense mutations from supplementary file S4 of De Rubeis et al. (2014) are as follows: R3439Q to R3441Q, G254V to G2737V, R156H to R2639H.
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Figure 2: The structure of Reelin is diagrammed with conserved domain boundaries mapped (NCBI Conserved Domain Database). (A) Missense, nonsense, and frameshift mutations that are absent in controls and thus more likely to contribute to ASD are indicated (*Bonora et al., 2003; @Neale et al., 2012; +Koshimizu et al., 2013; #De Rubeis et al., 2014; ∧Iossifov et al., 2014; ~Yuen et al., 2015; =Zhang et al., 2015). Specifically, mutations identified by Bonora et al. (2003) and De Rubeis et al. (2014) as occurring in isolated controls from case-control studies, even if they overlap with mutations identified in other studies, are not pictured. This process did not remove any RXR mutations identified in ASD probands; however, three RXR mutations were identified in controls: R1198H, R2104H, and R2292H. Missense mutations are colored based on PolyPhen2 predictions (green, benign; orange, possibly damaging; red, probably damaging). Nonsense and frameshift mutations are indicated in black. (B) Clustal Omega alignment of the sub-repeat domains is annotated with the corresponding missense mutations from (A). The RXR consensus sequence is indicated below the aligned repeat sequence. Note: corrections to annotations for missense mutations from supplementary file S4 of De Rubeis et al. (2014) are as follows: R3439Q to R3441Q, G254V to G2737V, R156H to R2639H.
Mentions: Large and small scale WES studies of ASD individuals consistently identify missense and nonsense mutations in RELN, leading researchers to emphasize its importance in ASD (De Rubeis et al., 2014). There are currently over 40 unique RELN variants identified in ASD probands that are absent in controls (Bonora et al., 2003; Neale et al., 2012; Koshimizu et al., 2013; De Rubeis et al., 2014; Iossifov et al., 2014; Yuen et al., 2015; Zhang et al., 2015; Figure 2). These mutations have not been functionally characterized; however, strong predictions regarding their consequences can be deduced based on Reelin structure and function.

Bottom Line: Several lines of evidence from multiple studies now implicate heterozygous mutations in RELN in autism spectrum disorders (ASD).The RELN mutations that are most clearly consequential are those that are predicted to inactivate the signaling function of the encoded protein and those that fall in a highly conserved RXR motif found at the core of the 16 Reelin subrepeats.Despite the growing evidence of RELN dysfunction in ASD, it appears that these mutations in isolation are insufficient and that secondary genetic or environmental factors are likely required for a diagnosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience and Physiology, SUNY Upstate Medical School Syracuse, NY, USA.

ABSTRACT
RELN encodes a large, secreted glycoprotein integral to proper neuronal positioning during development and regulation of synaptic function postnatally. Rare, homozygous, mutations lead to lissencephaly with cerebellar hypoplasia (LCH), accompanied by developmental delay and epilepsy. Until recently, little was known about the frequency or consequences of heterozygous mutations. Several lines of evidence from multiple studies now implicate heterozygous mutations in RELN in autism spectrum disorders (ASD). RELN maps to the AUTS1 locus on 7q22, and at this time over 40 distinct mutations have been identified that would alter the protein sequence, four of which are de novo. The RELN mutations that are most clearly consequential are those that are predicted to inactivate the signaling function of the encoded protein and those that fall in a highly conserved RXR motif found at the core of the 16 Reelin subrepeats. Despite the growing evidence of RELN dysfunction in ASD, it appears that these mutations in isolation are insufficient and that secondary genetic or environmental factors are likely required for a diagnosis.

No MeSH data available.


Related in: MedlinePlus