Recessive TMEM167A variants cause neonatal diabetes, microcephaly and epilepsy syndrome
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PROVIDER: PRJNA1291201 | ENA |
REPOSITORIES: ENA
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Project description:Understanding the genetic causes of diseases affecting pancreatic β cells and neurons can give insights into pathways essential for both cell types. Microcephaly, epilepsy and diabetes syndrome (MEDS) is a congenital disorder with two known aetiological genes, IER3IP1 and YIPF5. Both genes encode proteins involved in endoplasmic reticulum (ER) to Golgi trafficking. We used genome sequencing to identify 6 individuals with MEDS caused by biallelic variants in the novel disease gene, TMEM167A. All had neonatal diabetes (diagnosed <6 months) and severe microcephaly, five also had epilepsy. TMEM167A is highly expressed in developing and adult human pancreas and brain. To gain insights into the mechanisms leading to diabetes, we silenced TMEM167A in EndoC-βH1 cells and knocked-in one patient’s variant, p.Val59Glu, in induced pluripotent stem cells (iPSCs). Both TMEM167A depletion in EndoC-βH1 cells and the p.Val59Glu variant in iPSC-derived β cells sensitized β cells to ER stress. The p.Val59Glu variant impaired proinsulin trafficking to the Golgi and induced iPSC-β cell dysfunction. The discovery of TMEM167A variants as a new genetic cause of MEDS highlights a critical role of TMEM167A in the ER to Golgi pathway in β cells and neurons.
2025-08-18 | GSE302570 | GEO
Project description:Recessive TMEM167A variants cause neonatal diabetes, microcephaly and epilepsy syndrome [scRNA-seq]
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Project description:Understanding the genetic causes of diseases affecting pancreatic β cells and neurons can give insights into pathways essential for both cell types. Microcephaly, epilepsy and diabetes syndrome (MEDS) is a congenital disorder with two known aetiological genes, IER3IP1 and YIPF5. Both genes encode proteins involved in endoplasmic reticulum (ER) to Golgi trafficking. We used genome sequencing to identify 6 individuals with MEDS caused by biallelic variants in the novel disease gene, TMEM167A. All had neonatal diabetes (diagnosed <6 months) and severe microcephaly, five also had epilepsy. TMEM167A is highly expressed in developing and adult human pancreas and brain. To gain insights into the mechanisms leading to diabetes, we silenced TMEM167A in EndoC-βH1 cells and knocked-in one patient’s variant, p.Val59Glu, in induced pluripotent stem cells (iPSCs). Both TMEM167A depletion in EndoC-βH1 cells and the p.Val59Glu variant in iPSC-derived β cells sensitized β cells to ER stress. The p.Val59Glu variant impaired proinsulin trafficking to the Golgi and induced iPSC-β cell dysfunction. The discovery of TMEM167A variants as a new genetic cause of MEDS highlights a critical role of TMEM167A in the ER to Golgi pathway in β cells and neurons.
2025-08-18 | GSE302421 | GEO
Project description:Autosomal recessive TPPII mutations cause a new human immunodeficiency
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Project description:Primary autosomal recessive microcepahly and Seckel syndrome spectrum disodrers (MCPH-SCKS) include a heterogenous group of autosomal recessive inherited diseases characterized by primary (congenital) microcephaly, the absence of visceral abnormalities and a variable degree of cognitive impairment, short stature and facial dysmorphism. Recently, biallelic mutations in the nuclear pore complex (NPC) component nucleoporin 85 gene (NUP85) were reported to cause steroid-resistant nephrotic syndrome (SRNS). Here we report that homozygous mutations in NUP85 can also cause MCPH-SCKS without SRNS and thereby expand the phenotypic spectrum of NUP85-linked diseases. Structural analysis predicts the identified NUP85 mutation to have neither an effect on NPC architecture nor on its interaction with other NUPs. We show that mutant NUP85 is, however, associated with a reduced number of NPCs, abnormal mitotic spindle morphology, altered expression levels of protein involved in of cytoskeletal dynamics and decreased cell viability in patient cells. These altered biological processes can explain the disease-causative nature of the mutant NUP85 associated with the human phenotype. Our results also indicates the link of common cellular mechanism involved in the MCPH-SCKS spectrum disorders and NUP85-associated diseases. In addition to the previous studies, our results broadened the phenotype spectrum of NUP85-specific human disease and emphasizes a role of NUP85 in the development of the nervous system.
2022-08-11 | PXD018838 | Pride
Project description:Mutations in the IER3IP1 (Immediate early response-3 interacting protein 1) gene can cause MEDS1 (microcephaly with simplified gyral pattern, epilepsy, and permanent neonatal diabetes syndrome-1), a severe disease leading to death in early childhood. The small endoplasmic reticulum-membrane protein IER3IP1 has a non-essential role in ER-Golgi transport. We here use secretome and cell-surface proteomics to show that the loss of IER3IP1 or expression of the pathogenic p.L78P-mutation causes ER retention of selective cell-surface receptors and secreted proteins involved in neuronal migration. This correlates with distension of ER membranes and increased lysosomal activity. Trafficking of the cargo receptor ERGIC53 and of KDEL-receptor 2 are impaired, the latter causing the aberrant secretion of ER-localized chaperones. In utero knock-down of IER3IP1 in brains of mouse embryos displays a morphological phenotype of newborn neurons. Taken together, our data provide hints on how the loss or mutation of a 10 kDa small ER-membrane protein can cause a fatal syndrome.
2023-12-01 | MSV000093547 | MassIVE
Project description:CNV are known to be a frequent cause of the autism spectrum disorders (ASD) and intellectual disabilities (ID). However, the clinical heterogeneity of both disorders causes the diagnostic efficacy of CNV analysis to be modest. We conclude that comorbidities such as microcephaly, facial dysmorphia and epilepsy increase the risk of the pathogenic CNV finding in patients with ID and ASD. However, the significance of these comorbidities differs between both groups and shows dependency on whether the patients were primarily classified as ID or ASD. We suggest that stratification of the patients according to their comorbidities before testing can increase the yield of the detection rate of pathogenic CNV in both groups. The likelihood of pathogenic CNV detection in ASD patients without any comorbidities is low. Therefore, the effectivity of CNV analysis in these cases is modest
2019-06-11 | GSE132453 | GEO
Project description:Neonatal diabetes is caused by single gene mutations reducing pancreatic β cell number or impairing β cell function. Understanding the genetic basis of rare diabetes subtypes highlights fundamental biological processes in β cells. We identified 6 patients from 5 families with homozygous mutations in the YIPF5 gene, which is involved in trafficking between the endoplasmic reticulum (ER) and the Golgi. All patients had neonatal/early-onset diabetes, severe microcephaly, and epilepsy. YIPF5 is expressed during human brain development, in adult brain and pancreatic islets. We used 3 human β cell models (YIPF5 silencing in EndoC-βH1 cells, YIPF5 knockout and mutation knockin in embryonic stem cells, and patient-derived induced pluripotent stem cells) to investigate the mechanism through which YIPF5 loss of function affects β cells. Loss of YIPF5 function in stem cell-derived islet cells resulted in proinsulin retention in the ER, marked ER stress, and β cell failure. Partial YIPF5 silencing in EndoC-βH1 cells and a patient mutation in stem cells increased the β cell sensitivity to ER stress-induced apoptosis. We report recessive YIPF5 mutations as the genetic cause of a congenital syndrome of microcephaly, epilepsy, and neonatal/early-onset diabetes, highlighting a critical role of YIPF5 in β cells and neurons. We believe this is the first report of mutations disrupting the ER-to-Golgi trafficking, resulting in diabetes.
| S-EPMC7685733 | biostudies-literature
Project description:Mutations in the IER3IP1 (Immediate Early Response-3 Interacting Protein 1) gene can give rise to MEDS1 (Microcephaly with Simplified Gyral Pattern, Epilepsy, and Permanent Neonatal Diabetes Syndrome-1), a severe condition leading to early childhood mortality. The small endoplasmic reticulum (ER)-membrane protein IER3IP1 plays a non-essential role in ER-Golgi transport. Here, we employed secretome and cell-surface proteomics to demonstrate that the absence of IER3IP1 or the presence of the pathogenic p.L78P mutation results in the retention of specific cell-surface receptors and secreted proteins crucial for neuronal migration within the ER. This phenomenon correlates with the distension of ER membranes and increased lysosomal activity. Notably, the trafficking of cargo receptor ERGIC53 and KDEL-receptor 2 is compromised, with the latter leading to the anomalous secretion of ER-localized chaperones. Our investigation extended to in-utero knock-down of Ier3ip1 in mouse embryo brains, revealing a morphological phenotype in newborn neurons. In summary, our findings provide insights into how the loss or mutation of a 10 kDa small ER-membrane protein can cause a fatal syndrome.
2024-06-21 | MSV000095101 | MassIVE
Project description:Biallelic loss-of-function variants of ZFTRAF1 cause neurodevelopmental disorder with microcephaly and hypotonia
| PRJNA951710 | ENA