Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease

Guo, Dongchuan; Duan, Xue Yan; Regalado, Ellen S.; Mellor‐Crummey, Lauren; Kwartler, Callie S.; Kim, Dong H.; Lieberman, Kenneth V.; Vries, Bert B.A. de; Pfundt, Rolph; Schinzel, Albert; Kotzot, Dieter; Shen, Xuetong; Yang, Min; Bamshad, Michael J.; Nickerson, Deborah A.; Gornik, Heather L.; Ganesh, Santhi K.; Braverman, Alan C.; Grange, Dorothy K.; Milewicz, Dianna M.

doi:10.1016/j.ajhg.2016.11.008

Cited by 58 publications

(66 citation statements)

References 32 publications

(51 reference statements)

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“…it has also found that YY1AP1 interact with oncogene MDM2, tumor suppressor gene VHL, tyrosine kinase receptor MAPK, proteasome protein UBC,EGLN3 and SMURF1 and transcription factor CEBPA while CHMP7 can interact with growth inhibitory protein VPS37A, proteasome protein TSG101 and variety of transporter proteins. The YY1AP1 is a component of the INO80 chromatin remodeling complex, which is responsible for transcriptional regulation, DNA repair, and replication [18]. In a recent study by Zhao X, they found that YY1AP1 may serve as a key molecular target for EpCAM(+) AFP(+) HCC subtype Which was attributed with poor prognosis and stem cell-like phenotype [8].…”

Section: Discussionmentioning

confidence: 99%

The pattern of gene copy number variations (CNVs) in hepatocellular carcinoma; in silico analysis

Ansari

Shahrisa

Tahmaseby

et al. 2020

Preprint

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Cancer-associated death is the second leading cause of death worldwide. Study of the involved molecular networks of cancers can identify the potential target for early diagnosis, efficient therapies, and predictive prognosis of patients with cancer. Copy number variations are one type of DNA mutations which has been connected with human cancers. The CNVs can be used to find the regions of the genome involved in cancer phenotypes. This study is aimed to perform genome-wide chromosomal CNVs in HCC samples to find hotspot regions of disease using in silico analysis. The obtained data showed that gain of chromosome 1q and loss of 8p were frequently observed in target cancerous tissues. All the gains and losses were associated with tumor grade and metastasis. However, the amplification of YY1AP1 (Yin Yang-1 Associated Protein 1) and deletion of CHMP7 (Charged Multivesicular Body Protein 7) were observed in most of patients. These expression levels of YY1AP1 and CHMP7 were also upregulated and downregulated in cancerous samples respectively. Additionally, these two genes interact with critical oncogene and tumor suppressor genes like MDM2 (Mouse double minute 2 homolog) and VHL (von Hippel-Lindau tumor suppressor) showing the potential of these genes in HCC pathogenesis. Based on the observed data we suggest the 1q and 8p as candidate regions for HCC for researches especially YY1AP1 and CHMP7 loci.

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Section: Discussionmentioning

confidence: 99%

The pattern of gene copy number variations (CNVs) in hepatocellular carcinoma; in silico analysis

Ansari

Shahrisa

Tahmaseby

et al. 2020

Preprint

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“…In contrast, this missense variant did not affect steady state protein levels or localization to the nucleus, but the mutant protein was degraded more rapidly compared with wild type YY1AP1. In smooth muscle cells, YY1AP1 protein levels increase transiently in response to transforming growth factor β1 (TGFβ1), which drives differentiation to a more contractile phenotype (Guo et al, ). The less stable p.Pro360Leu variant protein may alter the dynamics of YY1AP1 expression in response to stimuli like TGFβ1, which has the potential to impact the phenotype of the smooth muscle cells and contribute to the occlusive vascular disease seen in this patient.…”

Section: Discussionmentioning

confidence: 99%

“…After its first report in four members of a family from the United States (Grange et al, ), four additional unrelated cases were subsequently reported (Volonghi et al, ; Wallerstein et al, ; Weymann et al, ). The etiology of Grange syndrome is due to homozygous loss‐of‐function rare variants in YY1AP1 , which encodes a component of the INO80 chromatin‐remodeling complex (Guo et al, ). We report here a patient with vascular disease consistent with Grange syndrome and a rare homozygous missense variant in YY1AP1 (c.1079C>T, p.Pro360Leu), and demonstrate that this variant leads to YY1AP1 instability.…”

Section: Introductionmentioning

confidence: 99%

Grange syndrome due to homozygous YY1AP1 missense rare variants

Alamo

Kwartler

Regalado

et al. 2019

American J of Med Genetics Pt A

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Grange syndrome (OMIM 602531) is an autosomal recessive condition characterized by severe early onset vascular occlusive disease and variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. Grange syndrome is caused by homozygous or compound heterozygous loss-of-function variants in the YYA1P1 gene. We report on the case of a 53-year old female with novel homozygous missense variants in YYA1P1 (c.1079C>T, p.Pro360Leu), presenting with a history of brachysyndactyly, hypertension, and ischemic stroke. Imaging studies revealed stenosis of the bilateral internal carotid with extensive collateralization of cerebral vessels in a moyamoya-like pattern, along with stenosis in the splenic, common hepatic, celiac, left renal, and superior mesenteric arteries. Functional studies conducted with the patient's dermal fibroblasts suggest that the p.Pro360Leu variant decreases the stability of the YY1AP1 protein. This is the first report of a missense variant associated with Grange syndrome characterized by later onset of vascular disease and a lack of developmental delay and bone fragility.

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“…Recently, Guo and co-workers [ 44 ] conducted a whole-exome-sequencing analysis on DNA from two affected siblings of the first reported family affected by Grange syndrome. This is a unique autosomal recessive syndrome, characterized by arterial stenosis that is similar to focal FMD in angiographic appearance and distribution, congenital cardiac defects, brachydactyly, syndactyly, bone fragility and learning disabilities [ 45 ].…”

Section: Current Knowledge From Genetic Studiesmentioning

confidence: 99%

“…This is a unique autosomal recessive syndrome, characterized by arterial stenosis that is similar to focal FMD in angiographic appearance and distribution, congenital cardiac defects, brachydactyly, syndactyly, bone fragility and learning disabilities [ 45 ]. Using very stringent filtering criteria, and by retaining only loss-of-function mutations, whole exome sequencing led to the identification of two compound heterozygous loss-of-function mutations in the YY1 associated protein 1 gene ( YY1AP1 ) in the two siblings [ 44 ]. Sanger sequencing confirmed the presence of both YY1AP1 mutations in the third affected sibling.…”

Section: Current Knowledge From Genetic Studiesmentioning

confidence: 99%

Genomics of Fibromuscular Dysplasia

Monaco

Georges

Lengelé

et al. 2018

IJMS

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Fibromuscular Dysplasia (FMD) is “an idiopathic, segmental, non-atherosclerotic and non-inflammatory disease of the musculature of arterial walls, leading to stenosis of small and medium-sized arteries” (Persu, et al; 2014). FMD can lead to hypertension, arterial dissections, subarachnoid haemorrhage, stroke or mesenteric ischemia. The pathophysiology of the disease remains elusive. While familial cases are rare (<5%) in contemporary FMD registries, there is evidence in favour of the existence of multiple genetic factors involved in this vascular disease. Recent collaborative efforts allowed the identification of a first genetic locus associated with FMD. This intronic variant located in the phosphatase and actin regulator 1 gene (PHACTR1) may influence the transcription activity of the endothelin-1 gene (EDN1) located nearby on chromosome 6. Interestingly, the PHACTR1 locus has also been involved in vascular hypertrophy in normal subjects, carotid dissection, migraine and coronary artery disease. National and international registries of FMD patients, with deep and harmonised phenotypic and genetic characterisation, are expected to be instrumental to improve our understanding of the genetic basis and pathophysiology of this intriguing vascular disease.

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Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease

Cited by 58 publications

References 32 publications

The pattern of gene copy number variations (CNVs) in hepatocellular carcinoma; in silico analysis

The pattern of gene copy number variations (CNVs) in hepatocellular carcinoma; in silico analysis

Grange syndrome due to homozygous YY1AP1 missense rare variants

Genomics of Fibromuscular Dysplasia

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