ArticleAmerican journal of human genetics2022
Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism.
Article in American journal of human genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 2 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
25 citing papers in PubMed, 2 syntheses or guidelines pooled it, 39 citations in OpenAlex.
- Dysmorphic syndromes with overgrowth - systematic review, part 2: chromosomal and epigenetic disorders and disorders associated with dynamic mutations.Pediatric endocrinology, diabetes, and metabolism · 2026Pooled it
- Consensus guideline for the diagnosis and management of pituitary adenomas in childhood and adolescence: Part 1, general recommendations.Nature reviews. Endocrinology · 2024Guideline
- Article
- Diverse SOX3 genetic variants and their associated phenotypic spectrum in human disease.Endocrine reviews · 2026Review
- The germline landscape of pituitary adenomas: established and emerging predisposition genes.The Journal of clinical endocrinology and metabolism · 2026Review
- Genetics of familial acromegaly and pituitary gigantism.The Journal of clinical endocrinology and metabolism · 2026Review
- Distinguishing benign from pathogenic duplications involving GPR101 and VGLL1-adjacent enhancers in the clinical setting with the bioinformatic tool POSTRE.NPJ genomic medicine · 2026Article
- Gpr101 expression during early stages of murine development.Gene expression patterns : GEP · 2025Article
- Structural variants in the 3D genome as drivers of disease.Nature reviews. Genetics · 2025Review
- Comparing models and experimental structures of the GPR101 receptor: Artificial intelligence yields highly accurate models.Journal of molecular graphics & modelling · 2025Article
- Article
- Enhancer adoption by an LTR retrotransposon generates viral-like particles, causing developmental limb phenotypes.Nature genetics · 2025Article
- Progress report on multiple endocrine neoplasia type 1.Familial cancer · 2025Review
- Chromatin conformation capture in the clinic: 4C-seq/HiC distinguishes pathogenic from neutral duplications at the GPR101 locus.Genome medicine · 2024Article
- Three-dimensional chromatin landscapes in somatotroph tumour.Clinical and translational medicine · 2024Article
- Stochasticity in genetics and gene regulation.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2024Review
- GPR101: Modeling a constitutively active receptor linked to X-linked acrogigantism.Journal of molecular graphics & modelling · 2024Article
- Case report: Management of pediatric gigantism caused by the TADopathy, X-linked acrogigantism.Frontiers in endocrinology · 2024Article
- Genomic structural variation: A complex but important driver of human evolution.American journal of biological anthropology · 2023Review
- Three-dimensional genome structure and function.MedComm · 2023Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
16 authors at 6 institutions in 6 countries.
Funding
Abstract
X-linked acrogigantism (X-LAG) is the most severe form of pituitary gigantism and is characterized by aggressive growth hormone (GH)-secreting pituitary tumors that occur in early childhood. X-LAG is associated with chromosome Xq26.3 duplications (the X-LAG locus typically includes VGLL1, CD40LG, ARHGEF6, RBMX, and GPR101) that lead to massive pituitary tumoral expression of GPR101, a novel regulator of GH secretion. The mechanism by which the duplications lead to marked pituitary misexpression of GPR101 alone was previously unclear. Using Hi-C and 4C-seq, we characterized the normal chromatin structure at the X-LAG locus. We showed that GPR101 is located within a topologically associating domain (TAD) delineated by a tissue-invariant border that separates it from centromeric genes and regulatory sequences. Next, using 4C-seq with GPR101, RBMX, and VGLL1 viewpoints, we showed that the duplications in multiple X-LAG-affected individuals led to ectopic interactions that crossed the invariant TAD border, indicating the existence of a similar and consistent mechanism of neo-TAD formation in X-LAG. We then identified several pituitary active cis-regulatory elements (CREs) within the neo-TAD and demonstrated in vitro that one of them significantly enhanced reporter gene expression. At the same time, we showed that the GPR101 promoter permits the incorporation of new regulatory information. Our results indicate that X-LAG is a TADopathy of the endocrine system in which Xq26.3 duplications disrupt the local chromatin architecture forming a neo-TAD. Rewiring GPR101-enhancer interaction within the new regulatory unit is likely to cause the high levels of aberrant expression of GPR101 in pituitary tumors caused by X-LAG.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.