DIA1R Is an X-Linked Gene Related to Deleted In Autism-1

Aziz, Azhari; Harrop, Sean P.; Bishop, Naomi

doi:10.1371/journal.pone.0014534

Cited by 25 publications

(30 citation statements)

References 160 publications

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“…On the other hand, we have identified a heterozygous truncating mutation in CXorf36, which was suggested by Aziz et al (2011a) to be linked causally to autism and X-linked intellectual disability, in one female patient but also in the hemizygous state in her healthy brother. This strongly argues against the proposed designation of CXorf36 as an X-linked intellectual disability gene.…”

Section: Ces and Novel Disease Gene Discoverymentioning

confidence: 93%

High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mendelian disorders

et al. 2015

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Clinical exome sequencing (CES) has become an increasingly popular diagnostic tool in patients with heterogeneous genetic disorders, especially in those with neurocognitive phenotypes. Utility of CES in consanguineous populations has not yet been determined on a large scale. A clinical cohort of 149 probands from Qatar with suspected Mendelian, mainly neurocognitive phenotypes, underwent CES from July 2012 to June 2014. Intellectual disability and global developmental delay were the most common clinical presentations but our cohort displayed other phenotypes, such as epilepsy, dysmorphism, microcephaly and other structural brain anomalies and autism. A pathogenic or likely pathogenic mutation, including pathogenic CNVs, was identified in 89 probands for a diagnostic yield of 60%. Consanguinity and positive family history predicted a higher diagnostic yield. In 5% (7/149) of cases, CES implicated novel candidate disease genes (MANF, GJA9, GLG1, COL15A1, SLC35F5, MAGE4, NEUROG1). CES uncovered two coexisting genetic disorders in 4% (6/149) and actionable incidental findings in 2% (3/149) of cases. Average time to diagnosis was reduced from 27 to 5 months. CES, which already has the highest diagnostic yield among all available diagnostic tools in the setting of Mendelian disorders, appears to be particularly helpful diagnostically in the highly consanguineous Middle Eastern population.

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Section: Ces and Novel Disease Gene Discoverymentioning

confidence: 93%

High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mendelian disorders

et al. 2015

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“…Interestingly, several proteins related to VLK also localize in the secretory pathway and are predicted to have a kinase-like fold (Figure 1B and Figure S1) (Dudkiewicz et al, 2013). These proteins are poorly characterized molecularly; however, several of them have been genetically linked to neurological disorders, including Deleted in Autism-1 (DIA1) and DIA1-Related (DIA1R) (Aziz et al, 2011a, b; Morrow et al, 2008; Tennant-Eyles et al, 2011). …”

Section: Introductionmentioning

confidence: 99%

A Single Kinase Generates the Majority of the Secreted Phosphoproteome

Tagliabracci

Wiley

Guo

et al. 2015

Cell

289

365

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Summary The existence of extracellular phosphoproteins has been acknowledged for over a century. However, research in this area has been undeveloped largely because the kinases that phosphorylate secreted proteins have escaped identification. Fam20C is a kinase that phosphorylates S-x-E/pS motifs on proteins in milk and in the extracellular matrix of bones and teeth. Here, we show that Fam20C generates the majority of the extracellular phosphoproteome. Using CRISPR/Cas9 genome editing, mass spectrometry, and biochemistry, we identify more than 100 secreted phosphoproteins as genuine Fam20C substrates. Further, we show that Fam20C exhibits broader substrate specificity than previously appreciated. Functional annotations of Fam20C substrates suggest roles for the kinase beyond biomineralization, including lipid homeostasis, wound healing, and cell migration and adhesion. Our results establish Fam20C as the major secretory pathway protein kinase and serve as a foundation for new areas of investigation into the role of secreted protein phosphorylation in human biology and disease.

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“…Third, 1190002N15Rik was the only gene down-regulated in the Mip−/− lens and the Lop/+ lens at both P1 and P7 [24]. 1190002N15Rik encodes a secreted Golgi protein (GoPro49), also known as deleted in autism protein 1 homolog (DIA1) or hypoxia and Akt-induced stem cell factor (HASF), that possesses cytoprotective and anti-apoptotic properties; however, its role in the lens secretory pathway is unclear [38–40]. Finally, Hspb1 was moderately down-regulated in the Mip−/− lens at P1 and strongly down-regulated in the Lop/+ lens at P1 and P7.…”

Section: Discussionmentioning

confidence: 99%

Lens transcriptome profile during cataract development in Mip-null mice

Bennett

Zhou

Shiels

2016

Biochemical and Biophysical Research Communications

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Major intrinsic protein or aquaporin-0 (MIP/AQP0) functions as a water channel and a cell-junction molecule in the vertebrate eye lens. Loss of MIP function in the lens leads to degraded optical quality and cataract formation by pathogenic mechanisms that are unclear. Here we have used microarray-hybridization analysis to detect lens transcriptome changes during cataract formation in mice that are functionally null for MIP (Mip−/−). In newborn Mip−/− lenses (P1) 11 genes were up-regulated and 18 were down-regulated (>2-fold, p=<0.05) and a similar number of genes was differentially regulated at P7. The most up-regulated genes (>6-fold) in the Mip−/− lens at P1 included those coding for a mitochondrial translocase (Timmdc1), a matrix metallopeptidase (Mmp2), a Rho GTPase-interacting protein (Ubxn11) and a transcription factor (Twist2). Apart from Mip, the most down-regulated genes (>4-fold) in the Mip−/− lens at P1 included those coding for a proteasome sub-unit (Psmd8), a ribonuclease (Pop4), and a heat-shock protein (Hspb1). Lens fiber cell degeneration in the Mip−/− lens was associated with increased numbers of TUNEL-positive cell nuclei and dramatically elevated levels of calpain-mediated proteolysis of αII-spectrin. However red-ox status, measured by glutathione and free-radical levels, was similar to that of wild-type. These data suggest that while relatively few genes (~1.5% of the transcriptome) were differentially regulated >2-fold in the Mip−/− lens, calpain hyper-activation acts as a terminal pathogenic event during lens fiber cell death and cataract formation.

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DIA1R Is an X-Linked Gene Related to Deleted In Autism-1

Cited by 25 publications

References 160 publications

High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mendelian disorders

High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mendelian disorders

A Single Kinase Generates the Majority of the Secreted Phosphoproteome

Lens transcriptome profile during cataract development in Mip-null mice

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