Dataset Information

Missense Variants in PAX4 Are Associated with Early-Onset Diabetes in Chinese.

ABSTRACT:

Introduction

East Asians are more susceptible to early-onset diabetes than Europeans and exhibit reduced insulin secretion at earlier stages. PAX4 plays a critical role in the development of ?-cells. The dysfunction-missense variants PAX4 R192H and PAX4 R192S are common in East Asians but rare in Europeans. Therefore, we aim to investigate the diabetes-associated genes, including PAX4 R192H/S, in East Asians with early-onset diabetes.

Methods

Exome variants of 80 Chinese early-onset diabetes patients (onset age?ResultsThe gene panel detected 11 monogenic diabetes patients with five novel mutations among the 80 early-onset diabetes patients. Asian-specifically enriched PAX4 R192H and R192S were associated with early-onset diabetes (R192H: OR 1.88, 95% CI 1.37-2.60, P?=?8.41?×?10^-5; R192S: OR 1.71, 95% CI 1.17-2.51, P?=?0.005). In early-onset diabetes patients, PAX4 R192H carriers had higher haemoglobin A1c (HbA1c) levels (P?=?0.030) and lower 2 h C-peptide levels in the oral glucose tolerance test (OGTT) (P?=?0.040); R192S carriers had lower fasting C-peptide (FCP) (P?=?0.011) and 2 h C-peptide levels (P?=?0.033) in OGTT than non-variant carriers.

Conclusions

The ethnic-specific enrichment of PAX4 R192H/S predisposing East Asians to early-onset diabetes with decreased C-peptide levels may be one explanation of the discrepancy of diabetes between East Asians and Europeans.

Clinical trial registration

ClinicalTrials.gov (NCT01938365).

SUBMITTER: Gao A

PROVIDER: S-EPMC7843779 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Missense Variants in PAX4 Are Associated with Early-Onset Diabetes in Chinese.

Gao Aibo A Gu Bin B Zhang Juan J Fang Chen C Su Junlei J Li Haorong H Han Rulai R Ye Lei L Wang Weiqing W Ning Guang G Wang Jiqiu J Gu Weiqiong W

Diabetes therapy : research, treatment and education of diabetes and related disorders 20201120 1

<h4>Introduction</h4>East Asians are more susceptible to early-onset diabetes than Europeans and exhibit reduced insulin secretion at earlier stages. PAX4 plays a critical role in the development of β-cells. The dysfunction-missense variants PAX4 R192H and PAX4 R192S are common in East Asians but rare in Europeans. Therefore, we aim to investigate the diabetes-associated genes, including PAX4 R192H/S, in East Asians with early-onset diabetes.<h4>Methods</h4>Exome variants of 80 Chinese early-ons ...[more]

PMID: 33216280

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Project description:ObjectiveThe study was undertaken to identify a monogenic cause of early onset, generalized dystonia.MethodsMethods consisted of genome-wide linkage analysis, exome and Sanger sequencing, clinical neurological examination, brain magnetic resonance imaging, and protein expression studies in skin fibroblasts from patients.ResultsWe identified a heterozygous variant, c.388G>A, p.Gly130Arg, in the eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2) gene, segregating with early onset isolated generalized dystonia in 5 patients of a Taiwanese family. EIF2AK2 sequencing in 191 unrelated patients with unexplained dystonia yielded 2 unrelated Caucasian patients with an identical heterozygous c.388G>A, p.Gly130Arg variant, occurring de novo in one case, another patient carrying a different heterozygous variant, c.413G>C, p.Gly138Ala, and one last patient, born from consanguineous parents, carrying a third, homozygous variant c.95A>C, p.Asn32Thr. These 3 missense variants are absent from gnomAD, and are located in functional domains of the encoded protein. In 3 patients, additional neurological manifestations were present, including intellectual disability and spasticity. EIF2AK2 encodes a kinase (protein kinase R [PKR]) that phosphorylates eukaryotic translation initiation factor 2 alpha (eIF2α), which orchestrates the cellular stress response. Our expression studies showed abnormally enhanced activation of the cellular stress response, monitored by PKR-mediated phosphorylation of eIF2α, in fibroblasts from patients with EIF2AK2 variants. Intriguingly, PKR can also be regulated by PRKRA (protein interferon-inducible double-stranded RNA-dependent protein kinase activator A), the product of another gene causing monogenic dystonia.InterpretationWe identified EIF2AK2 variants implicated in early onset generalized dystonia, which can be dominantly or recessively inherited, or occur de novo. Our findings provide direct evidence for a key role of a dysfunctional eIF2α pathway in the pathogenesis of dystonia. ANN NEUROL 2021;89:485-497.

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Dataset Information

Missense Variants in PAX4 Are Associated with Early-Onset Diabetes in Chinese.

Introduction

Methods

Conclusions

Clinical trial registration

Publications

Missense Variants in PAX4 Are Associated with Early-Onset Diabetes in Chinese.

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