Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism

Franke, Martin; Daly, Adrian; Palmeira, Léonor; Tirosh, Amir; Stigliano, Antonio; Trifan, Eszter; Faucz, Fabio R.; Abboud, Dayana; Pétrossians, Patrick; Tena, Juan J.; Vitali, Eleonora; Lania, Andrea; Gómez-Skármeta, José Luis; Beckers, Albert; Stratakis, Constantine A.; Trivellin, Giampaolo

doi:10.1016/j.ajhg.2022.02.002

Cited by 20 publications

(17 citation statements)

References 65 publications

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“…A general framework of approximately one causal gene per phenotype per segment is in agreement with the increased density of constrained genes we observed for pleiotropic rCNVs and comports with existing knowledge for a handful of prominent GDs, such as CRKL and TBX1 associations with kidney and heart abnormalities, respectively, in 22q11.2 GD deletions (Lindsay et al, 2001;Lopez-Rivera et al, 2017). However, the full genetic effects of most rCNVs are likely to be more complex, given the known examples of cis-regulatory effects (Franke et al, 2022), gene-gene interactions (Carvalho et al, 2014;Singh et al, 2020), and variable penetrance or expressivity due to secondary variants and polygenic background (Albers et al, 2012;Davies et al, 2020;Girirajan et al, 2012).…”

Section: Discussionsupporting

confidence: 85%

A cross-disorder dosage sensitivity map of the human genome

Collins

Glessner

Porcu

et al. 2022

Cell

140

108

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Section: Discussionsupporting

confidence: 85%

A cross-disorder dosage sensitivity map of the human genome

Collins

Glessner

Porcu

et al. 2022

Cell

140

108

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“…We initially identified a deleterious missense PAM variant (p.Arg703Gln) in a FIPA family with a severe form of childhood-onset pituitary gigantism in which other established causes, such as X-linked acrogigantism (X-LAG) due to duplications involving GPR101 , germline AIP mutations/deletions or others, had been ruled out [33, 34]. Among the genes filtered from the WES screening, the high level of PAM expression in the pituitary gland and its known functions in the pituitary and other endocrine cells made PAM the prioritized candidate.…”

Section: Discussionmentioning

confidence: 99%

Germline loss-of-functionPAMvariants are enriched in subjects with pituitary hypersecretion

Trivellin

Daly

Hernández-Ramírez

et al. 2023

Preprint

Self Cite

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Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. Following the identification of a loss-of-function variant (p.Arg703Gln) in the PAM gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated pituitary adenomas kindreds for PAM variants. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis. No germline CNVs or somatic single nucleotide variants (SNVs) were identified. We detected seven likely pathogenic heterozygous missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with GH excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or with different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, for splicing by minigene assays, and for amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs to diagnoses linked to pituitary gland hyperfunction. Identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.

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“…Indeed, deletions encompassing TAD boundaries will fuse the two adjacent TADs (TAD fusion) (Figure 4B). [63,[93][94][95][96] Duplications that include TAD boundaries will create new TADs ("neo-TAD" formation) (Figure 4C), [68,71,94,[96][97][98][99][100][101] and inversions encompassing TAD boundaries will result in the exchange of regulatory material between TADs (TAD shuffling) (Figure 4D).…”

Section: Enhancer Adoptionmentioning

confidence: 99%

Disruption of regulatory domains and novel transcripts as disease‐causing mechanisms

Allou

Mundlos

2023

BioEssays

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Deletions, duplications, insertions, inversions, and translocations, collectively called structural variations (SVs), affect more base pairs of the genome than any other sequence variant. The recent technological advancements in genome sequencing have enabled the discovery of tens of thousands of SVs per human genome. These SVs primarily affect non‐coding DNA sequences, but the difficulties in interpreting their impact limit our understanding of human disease etiology. The functional annotation of non‐coding DNA sequences and methodologies to characterize their three‐dimensional (3D) organization in the nucleus have greatly expanded our understanding of the basic mechanisms underlying gene regulation, thereby improving the interpretation of SVs for their pathogenic impact. Here, we discuss the various mechanisms by which SVs can result in altered gene regulation and how these mechanisms can result in rare genetic disorders. Beyond changing gene expression, SVs can produce novel gene‐intergenic fusion transcripts at the SV breakpoints.

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Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism

Cited by 20 publications

References 65 publications

A cross-disorder dosage sensitivity map of the human genome

A cross-disorder dosage sensitivity map of the human genome

Germline loss-of-functionPAMvariants are enriched in subjects with pituitary hypersecretion

Disruption of regulatory domains and novel transcripts as disease‐causing mechanisms

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