Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1041755 | ENA |
REPOSITORIES: ENA
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Project description:Genes involved in distinct diabetes types suggest shared disease mechanisms. We show that rare ONECUT1 coding variants cause monogenic recessive diabetes (neonatal or very early-onset, syndromic) in two unrelated patients, and monogenic dominant diabetes (early adult-onset) in heterozygous relatives of these and 13 additional unrelated cases. Patients heterozygous for rare ONECUT1 coding variants define a subgroup of T2D with early-onset diabetes and other features. In addition, common regulatory ONECUT1 variants are associated with multifactorial T2D. Directed differentiation of human pluripotent stem cells to the pancreatic lineage revealed that loss of ONECUT1 impairs pancreatic progenitor formation and a subsequent endocrine program. We uncovered that ONECUT1 activates the pro-endocrine genes NKX6.1 and NKX2.2 through binding to their cis-regulatory elements. Globally, ONECUT1-directed gene transcription occurs in association with major islet transcription factors, at clusters of pancreas- and endocrine-specific enhancers within open chromatin. ONECUT1 regulates a transcriptional and epigenetic machinery critical for proper endocrine pancreatic development, involved in a spectrum of diabetes, monogenic recessive and dominant, and multifactorial.
2021-11-03 | PXD018887 | Pride
Project description:Obesity is considered a multifactorial disorder with high heritability (50-75%), probably higher in early-onset and severe cases. Although rare monogenic forms and several genes and regions of susceptibility, including CNVs, have been defined, the genetic causes underlying the disease still remain largely unknown. We aimed to identify novel genetic and genomic abnormalities in a cohort of Spanish children with severe non-syndromic early-onset obesity (EOO). We obtained molecular karyotypes of 157 children with EOO. Large and rare CNVs were validated and segregated in the family. A higher burden of duplication-type CNVs was detected in EOO patients versus controls (OR=1.85, p-value=0.008).
2017-04-28 | E-MTAB-5680 | biostudies-arrayexpress
Project description:Up to 10% of patients with severe early-onset obesity carry pathogenic variants in known obesity-related genes, mostly affecting the leptin-melanocortin pathway. Studying children with severe obesity from consanguineous populations provides a unique opportunity to uncover novel molecular mechanisms. Using whole-exome sequencing, followed by a rigorous analytical and filtration strategy, we identified three different homozygous missense variants in SREK1 (encoding Splicing Regulatory glutamic acid and lysine rich protein) in Pakistani children with severe obesity, from three unrelated consanguineous pedigrees. The wild type SREK1 gene of human induced pluripotent stem cell (iPSC)-derived hypothalamic neurons was individually replaced by each of the three variants and the impact of these changes on global gene expression was studied. Neurons expressing the two variants in the SREK1 RNA recognition domain p.P95L and p.T194M, but not the C-terminally located p.E601K, had markedly reduced expression of the small nucleolar RNA clusters SNORD115 and SNORD116, deficiency of which has been implicated in Prader-Willi syndrome (PWS). In addition to hyperphagic obesity the carriers of these two variants had other features of PWS, such as neonatal hypotonia. In conclusion, homozygous variants in SREK1 result in a subtype of severe early onset obesity sharing features with PWS.
2025-06-05 | GSE292889 | GEO
Project description:Identification of candidate predisposing copy number variants in familial and early-onset colorectal cancer patients
| PRJNA110011 | ENA
Project description:SCOOP severe early-onset obesity cases
| EGAD00010000594 | EGA
Project description:FAMIN (LACC1, C13orf31) loss-of-function causes systemic juvenile idiopathic arthritis and very early-onset inflammatory bowel disease, while a common I254V substitution results in hypomorphic function and increases susceptibility to Crohn’s disease and leprosy. In this study, we compare the mRNA transcriptional profiles of M0, M1 and M2-polarised bone marrow-derived macrophages from mice engineered at their endogenous locus to express human non-risk (Faminp.254I), risk (Faminp.254V) and monogenic (Faminp.284R) disease variants.
2020-01-28 | GSE126641 | GEO
Project description:Diabetes is a complex genetic disease affecting millions of people worldwide. A common monogenic form of diabetes is glucokinase (GCK) maturity-onset diabetes of the young (GCK-MODY), which is caused by heterozygous inactivating variants in the gene encoding GCK. GCK catalyzes the phosphorylation of glucose and is known as the pancreatic glucose sensor. Patients with GCK-MODY, in contrast to other diabetics, often do not require treatment but are frequently misdiagnosed and treated unnecessarily. Genetic testing can prevent this, but is hampered by the challenge of interpreting genetic variants. To address this challenge, we generated a comprehensive map of human GCK variant activity. The activity map includes 97% of the possible missense and nonsense variants and correlate with in vitro catalytic efficiency, fasting glucose levels in patients and evolutionary conservation analysis. Activity scores include both hyper- and hypoactive variants.
2022-06-16 | GSE198878 | GEO
Project description:Human Core Exome Genotyping for 1456 severe early onset obesity cases (SCOOP)
| EGAD00010001623 | EGA