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DIA1R is an X-linked gene related to Deleted In Autism-1.

Aziz A, Harrop SP, Bishop NE - PLoS ONE (2011)

Bottom Line: Both genes are ubiquitously expressed, including in fetal and adult brain tissue.Examination of published literature revealed point mutations in DIA1R are associated with X-linked mental retardation (XLMR) and DIA1R deletion is associated with syndromes with ASD-like traits and/or XLMR.Together, these results support a model where the DIA1 and DIA1R gene products regulate molecular traffic through the cellular secretory pathway or affect the function of secreted factors, and functional deficits cause disorders with ASD-like symptoms and/or mental retardation.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, La Trobe University, Bundoora, Victoria, Australia.

ABSTRACT

Background: Autism spectrum disorders (ASDS) are frequently occurring disorders diagnosed by deficits in three core functional areas: social skills, communication, and behaviours and/or interests. Mental retardation frequently accompanies the most severe forms of ASDs, while overall ASDs are more commonly diagnosed in males. Most ASDs have a genetic origin and one gene recently implicated in the etiology of autism is the Deleted-In-Autism-1 (DIA1) gene.

Methodology/principal findings: Using a bioinformatics-based approach, we have identified a human gene closely related to DIA1, we term DIA1R (DIA1-Related). While DIA1 is autosomal (chromosome 3, position 3q24), DIA1R localizes to the X chromosome at position Xp11.3 and is known to escape X-inactivation. The gene products are of similar size, with DIA1 encoding 430, and DIA1R 433, residues. At the amino acid level, DIA1 and DIA1R are 62% similar overall (28% identical), and both encode signal peptides for targeting to the secretory pathway. Both genes are ubiquitously expressed, including in fetal and adult brain tissue.

Conclusions/significance: Examination of published literature revealed point mutations in DIA1R are associated with X-linked mental retardation (XLMR) and DIA1R deletion is associated with syndromes with ASD-like traits and/or XLMR. Together, these results support a model where the DIA1 and DIA1R gene products regulate molecular traffic through the cellular secretory pathway or affect the function of secreted factors, and functional deficits cause disorders with ASD-like symptoms and/or mental retardation.

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Related in: MedlinePlus

Microarray gene expression data for DIA1 and DIA1R.Graphical presentation of microarray expression data for (A) DIA1 or (B) DIA1R in normal, healthy human tissues. The intensity values (shown on the root-scale y-axis) are average values, where variation in the range of measurements is represented by a white box above the coloured minimal-measurement bar. Tissues are grouped according to their origin and the groups coloured: red  =  immune system; green  =  nervous system; yellow  =  muscle; blue  =  secretory glands; pink  =  ‘other’. Tissue abbreviation (on the x-axis) legend: BMR = bone marrow; SPL = spleen; TMS = thymus; BRN = brain; SPC = spinal cord; HRT = heart; MSL = skeletal muscle; LVR = liver; PNC = pancreas; PST = prostate; KDN = kidney; LNG = lung. Data were obtained from the GeneNote database of human genes at the Weizmann Institute [75], and are MAS5.0 normalized data obtained using the Affymetrix HG-U95 set A–E.
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pone-0014534-g004: Microarray gene expression data for DIA1 and DIA1R.Graphical presentation of microarray expression data for (A) DIA1 or (B) DIA1R in normal, healthy human tissues. The intensity values (shown on the root-scale y-axis) are average values, where variation in the range of measurements is represented by a white box above the coloured minimal-measurement bar. Tissues are grouped according to their origin and the groups coloured: red  =  immune system; green  =  nervous system; yellow  =  muscle; blue  =  secretory glands; pink  =  ‘other’. Tissue abbreviation (on the x-axis) legend: BMR = bone marrow; SPL = spleen; TMS = thymus; BRN = brain; SPC = spinal cord; HRT = heart; MSL = skeletal muscle; LVR = liver; PNC = pancreas; PST = prostate; KDN = kidney; LNG = lung. Data were obtained from the GeneNote database of human genes at the Weizmann Institute [75], and are MAS5.0 normalized data obtained using the Affymetrix HG-U95 set A–E.

Mentions: Microarray data from two sources (Figures 4, S2, and S3) supported the findings of the EST profiling results, as ubiquitous expression of both DIA1 and DIA1R was found, including expression in brain tissue. Microarray expression levels of human DIA1 were strikingly similar in all tissue types tested, but no confirmation of higher levels in ‘mouth’ tissues (tonsil, trachea, salivary gland, and tongue, being the comparable microarray tissue data), vascular tissue (CD105+ circulating endothelial cells being the closest microarray data), or mammary gland (no comparable microarray data) detected by EST profiling was found by microarray analysis. By microarray analysis, the highest level of DIA1 was found in BDCA-4 (blood dendritic cell antigen 4 or neuropilin-1 or CD304) -positive plasmacytoid dendritic cells (Figure S2), which secrete high levels of type I interferons [86]. By contrast to the DIA1 microarray data, microarray expression levels of DIA1R were less uniform (Figures 4 and S3). However, the highest DIA1R expression level found in the Gene Atlas microarray, which was found in liver (Figure S3), was not supported by the GeneNote microarray data (Figure 4). Within brain tissue, the highest expression level of DIA1R was in the cerebellar peduncles (Figure S3), a region of the brain abnormal in those with ASD [87]–[89]. However, microarray studies are plagued by a lack of reproducibility and accuracy [90]–[93], and we can not place too much emphasis on differences between gene expression levels, but must focus on overall expression profiles. While quantitative reverse-transcriptase polymerase chain reactions (RT-PCR) can provide more accurate and reproducible results [94], and can be used in conjunction with commercially available human tissue panels, analysis of data from this approach relies on the choice of reference gene for normalization [95]. Changes in the comparable housekeeping gene can lead to changes in the significance and expression of the target gene using RT-PCR approaches to quantifying gene expression [96], [97]. We can therefore only reliably conclude that human DIA1 and DIA1R are both ubiquitously expressed genes.


DIA1R is an X-linked gene related to Deleted In Autism-1.

Aziz A, Harrop SP, Bishop NE - PLoS ONE (2011)

Microarray gene expression data for DIA1 and DIA1R.Graphical presentation of microarray expression data for (A) DIA1 or (B) DIA1R in normal, healthy human tissues. The intensity values (shown on the root-scale y-axis) are average values, where variation in the range of measurements is represented by a white box above the coloured minimal-measurement bar. Tissues are grouped according to their origin and the groups coloured: red  =  immune system; green  =  nervous system; yellow  =  muscle; blue  =  secretory glands; pink  =  ‘other’. Tissue abbreviation (on the x-axis) legend: BMR = bone marrow; SPL = spleen; TMS = thymus; BRN = brain; SPC = spinal cord; HRT = heart; MSL = skeletal muscle; LVR = liver; PNC = pancreas; PST = prostate; KDN = kidney; LNG = lung. Data were obtained from the GeneNote database of human genes at the Weizmann Institute [75], and are MAS5.0 normalized data obtained using the Affymetrix HG-U95 set A–E.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3022024&req=5

pone-0014534-g004: Microarray gene expression data for DIA1 and DIA1R.Graphical presentation of microarray expression data for (A) DIA1 or (B) DIA1R in normal, healthy human tissues. The intensity values (shown on the root-scale y-axis) are average values, where variation in the range of measurements is represented by a white box above the coloured minimal-measurement bar. Tissues are grouped according to their origin and the groups coloured: red  =  immune system; green  =  nervous system; yellow  =  muscle; blue  =  secretory glands; pink  =  ‘other’. Tissue abbreviation (on the x-axis) legend: BMR = bone marrow; SPL = spleen; TMS = thymus; BRN = brain; SPC = spinal cord; HRT = heart; MSL = skeletal muscle; LVR = liver; PNC = pancreas; PST = prostate; KDN = kidney; LNG = lung. Data were obtained from the GeneNote database of human genes at the Weizmann Institute [75], and are MAS5.0 normalized data obtained using the Affymetrix HG-U95 set A–E.
Mentions: Microarray data from two sources (Figures 4, S2, and S3) supported the findings of the EST profiling results, as ubiquitous expression of both DIA1 and DIA1R was found, including expression in brain tissue. Microarray expression levels of human DIA1 were strikingly similar in all tissue types tested, but no confirmation of higher levels in ‘mouth’ tissues (tonsil, trachea, salivary gland, and tongue, being the comparable microarray tissue data), vascular tissue (CD105+ circulating endothelial cells being the closest microarray data), or mammary gland (no comparable microarray data) detected by EST profiling was found by microarray analysis. By microarray analysis, the highest level of DIA1 was found in BDCA-4 (blood dendritic cell antigen 4 or neuropilin-1 or CD304) -positive plasmacytoid dendritic cells (Figure S2), which secrete high levels of type I interferons [86]. By contrast to the DIA1 microarray data, microarray expression levels of DIA1R were less uniform (Figures 4 and S3). However, the highest DIA1R expression level found in the Gene Atlas microarray, which was found in liver (Figure S3), was not supported by the GeneNote microarray data (Figure 4). Within brain tissue, the highest expression level of DIA1R was in the cerebellar peduncles (Figure S3), a region of the brain abnormal in those with ASD [87]–[89]. However, microarray studies are plagued by a lack of reproducibility and accuracy [90]–[93], and we can not place too much emphasis on differences between gene expression levels, but must focus on overall expression profiles. While quantitative reverse-transcriptase polymerase chain reactions (RT-PCR) can provide more accurate and reproducible results [94], and can be used in conjunction with commercially available human tissue panels, analysis of data from this approach relies on the choice of reference gene for normalization [95]. Changes in the comparable housekeeping gene can lead to changes in the significance and expression of the target gene using RT-PCR approaches to quantifying gene expression [96], [97]. We can therefore only reliably conclude that human DIA1 and DIA1R are both ubiquitously expressed genes.

Bottom Line: Both genes are ubiquitously expressed, including in fetal and adult brain tissue.Examination of published literature revealed point mutations in DIA1R are associated with X-linked mental retardation (XLMR) and DIA1R deletion is associated with syndromes with ASD-like traits and/or XLMR.Together, these results support a model where the DIA1 and DIA1R gene products regulate molecular traffic through the cellular secretory pathway or affect the function of secreted factors, and functional deficits cause disorders with ASD-like symptoms and/or mental retardation.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, La Trobe University, Bundoora, Victoria, Australia.

ABSTRACT

Background: Autism spectrum disorders (ASDS) are frequently occurring disorders diagnosed by deficits in three core functional areas: social skills, communication, and behaviours and/or interests. Mental retardation frequently accompanies the most severe forms of ASDs, while overall ASDs are more commonly diagnosed in males. Most ASDs have a genetic origin and one gene recently implicated in the etiology of autism is the Deleted-In-Autism-1 (DIA1) gene.

Methodology/principal findings: Using a bioinformatics-based approach, we have identified a human gene closely related to DIA1, we term DIA1R (DIA1-Related). While DIA1 is autosomal (chromosome 3, position 3q24), DIA1R localizes to the X chromosome at position Xp11.3 and is known to escape X-inactivation. The gene products are of similar size, with DIA1 encoding 430, and DIA1R 433, residues. At the amino acid level, DIA1 and DIA1R are 62% similar overall (28% identical), and both encode signal peptides for targeting to the secretory pathway. Both genes are ubiquitously expressed, including in fetal and adult brain tissue.

Conclusions/significance: Examination of published literature revealed point mutations in DIA1R are associated with X-linked mental retardation (XLMR) and DIA1R deletion is associated with syndromes with ASD-like traits and/or XLMR. Together, these results support a model where the DIA1 and DIA1R gene products regulate molecular traffic through the cellular secretory pathway or affect the function of secreted factors, and functional deficits cause disorders with ASD-like symptoms and/or mental retardation.

Show MeSH
Related in: MedlinePlus