Multiple roles of Ulk4 in neurogenesis and brain function

Liu, Min; Xu, Ping; O’Brien, Timothy; Shen, Sanbing

doi:10.1080/23262133.2017.1313646

Cited by 14 publications

(13 citation statements)

References 37 publications

(42 reference statements)

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“…Its deficiency leads to hypomyelination, 56 and it has been associated with neuropsychiatric traits. 57 Finally, we report a novel association on chromosome 18, located between ZBTB14, encoding a zinc finger transcription factor (zinc finger and BTB domaincontaining protein 14), and EPB41L3, encoding for a membrane protein that inhibits cell proliferation and promotes apoptosis (erythrocyte mem brane protein band 4•1like 3).…”

Section: Discussionmentioning

confidence: 94%

Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies

Traylor

Persyn

Tomppo

et al. 2021

The Lancet Neurology

111

129

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Background The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease. MethodsWe did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation.Findings Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 con trols, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associa ted with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP,

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Section: Discussionmentioning

confidence: 94%

Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies

Traylor

Persyn

Tomppo

et al. 2021

The Lancet Neurology

111

129

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“…So far, little is known about the function of LGI2, apart from its association with epilepsies (Limviphuvadh et al, 2010). ULK4 has several functions in the brain including involvement in neuronal cell proliferation and cell-cycle regulation, whereas functions outside the central nervous system are largely unknown (Liu et al, 2017). Considering current functional information, the GWAS results propose Thioredoxin Related Transmembrane Protein 1 ( TMX1 ) on SSC1 and Receptor-Type Tyrosine-Protein Phosphatase T ( PTPRT ) on SSC17 as the most interesting positional and functional candidate genes.…”

Section: Discussionmentioning

confidence: 99%

Genetic Contribution to Variation in Blood Calcium, Phosphorus, and Alkaline Phosphatase Activity in Pigs

et al. 2019

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Blood values of calcium (Ca), inorganic phosphorus (IP), and alkaline phosphatase activity (ALP) are valuable indicators for mineral status and bone mineralization. The mineral homeostasis is maintained by absorption, retention, and excretion processes employing a number of known and unknown sensing and regulating factors with implications on immunity. Due to the high inter-individual variation of Ca and P levels in the blood of pigs and to clarify molecular contributions to this variation, the genetics of hematological traits related to the Ca and P balance were investigated in a German Landrace population, integrating both single-locus and multi-locus genome-wide association study (GWAS) approaches. Genomic heritability estimates suggest a moderate genetic contribution to the variation of hematological Ca ( N = 456), IP ( N = 1049), ALP ( N = 439), and the Ca/P ratio ( N = 455), with values ranging from 0.27 to 0.54. The genome-wide analysis of markers adds a number of genomic regions to the list of quantitative trait loci, some of which overlap with previous results. Despite the gaps in knowledge of genes involved in Ca and P metabolism, genes like THBS2 , SHH , PTPRT , PTGS1 , and FRAS1 with reported connections to bone metabolism were derived from the significantly associated genomic regions. Additionally, genomic regions included TRAFD1 and genes coding for phosphate transporters ( SLC17A1 – SLC17A4 ), which are linked to Ca and P homeostasis. The study calls for improved functional annotation of the proposed candidate genes to derive features involved in maintaining Ca and P balance. This gene information can be exploited to diagnose and predict characteristics of micronutrient utilization, bone development, and a well-functioning musculoskeletal system in pig husbandry and breeding.

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“…Ciliary disorders may be isolated or syndromic, and common features are cystic liver and/or kidney disease, blindness, neural tube defects, brain anomalies and intellectual disability, skeletal abnormalities ranging from polydactyly to abnormally short ribs and limbs, ectodermal defects, obesity, situs inversus, infertility, and recurrent respiratory tract infections [Oud et al, 2017]. Liu et al [2017Liu et al [ , 2018b, demonstrated that ULK4 is also a crucial regulator of myelination. Moreover, Liu et al [2018 a ] have shown for the first time that Ulk4 haploinsufficiency in mice leads to increased anxiety-related behavior with disturbed GABAergic signaling.…”

Section: Discussionmentioning

confidence: 99%

Intragenic Microdeletion of ULK4 and Partial Microduplication of BRWD3 in Siblings with Neuropsychiatric Features and Obesity

Tassano¹,

Uccella²,

Giacomini³

et al. 2018

Cytogenet Genome Res

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ULK4 and BRWD3 deletions have been identified in patients with developmental/language delay and intellectual disability. Both genes play pivotal roles in brain development. In particular, ULK4 encodes serine/threonine kinases that are critical for the development and function of the nervous system, while BRWD3 plays a crucial role in ubiquitination, as part of the ubiquitin/proteasome system. We report on 2 brothers, aged 7.6 and 20 years, presenting with cognitive impairment, epilepsy, autistic features, hearing loss, and obesity. Array-CGH analysis demonstrated 2 rare CNVs in both siblings: a paternally inherited microdeletion of ∼145 kb at 3p22.1, disrupting the ULK4 gene, and a maternally inherited microduplication of ∼117 kb at Xq21.1 including only the BRWD3 gene. As already described for other recurrent syndromes with variable phenotype, these findings are challenging in genetic counseling because of an evident variable penetrance. We discuss the possible correlations between the clinical phenotype of our patients and the function of the genes involved in these microrearrangements.

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Multiple roles of Ulk4 in neurogenesis and brain function

Cited by 14 publications

References 37 publications

Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies

Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies

Genetic Contribution to Variation in Blood Calcium, Phosphorus, and Alkaline Phosphatase Activity in Pigs

Intragenic Microdeletion of <b><i>ULK4</i></b> and Partial Microduplication of <b><i>BRWD3</i></b> in Siblings with Neuropsychiatric Features and Obesity

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