Genomic, transcriptomic, and protein landscape profile of CFTR and cystic fibrosis

Sanders, Morgan; Lawlor, James M.J.; Li, Xiaopeng; Schuen, John; Millard, Susan L.; Zhang, Xi; Buck, Leah; Grysko, Bethany; Uhl, Katie; Hinds, David A.; Stenger, Cynthia L.; Morris, Michele; Lamb, Neil E.; Levy, Hara; Bupp, Caleb; Prokop, Jeremy W.

doi:10.1007/s00439-020-02211-w

Cited by 4 publications

(3 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

Section: Discussionmentioning

confidence: 99%

“…These forms of dominant negative variants are the primary interest in mapping dominance for this paper. Other variants in proteins can exert different protein functional outcomes, with the most wellstudied example in the CFTR protein for cystic fibrosis, where variants can change protein abundance, localization, receptor activation, or ion transport based on the amino acid altered (Sanders et al, 2021 T A B L E 2 Top VUS that fit the dominant variant predictions based on pathogenic variant analysis Note: For each variant is annotated the protein it is found in, the # of the amino acid, the wild-type amino acid (AA), the variant (Var) amino acid, the conservation score (0-2), whether the variant is conserved in all sequence alignments or in the GRIN2 sequences (GRIN2A, GRIN2B, GRIN2C, GRIN2D), the root mean squared fluctuation (RMSF) of the molecular dynamics for the amino acid, the intra and inter molecular contacts based on DCCM, the predictions scores for damaging variants based on PolyPhen2/Provean/SIFT (score of 1 means its bad), and the summed variant score (0-7, with 7 high functional outcome prediction). a GRIN2A G760S is the individual from the Helen DeVos Children's hospital.…”

Section: Vus Of High Impactmentioning

confidence: 99%

See 1 more Smart Citation

N‐methyl‐d‐aspartate (NMDA) receptor genetics: The power of paralog homology and protein dynamics in defining dominant genetic variants

Charron

Hernandez

Bilinovich

et al. 2021

American J of Med Genetics Pt A

Self Cite

View full text Add to dashboard Cite

Predicting genotype‐to‐phenotype correlations from genomic variants has been challenging, particularly for genes that have a complex balance of dominant and recessive inheritance for phenotypes. Variants in NMDA receptor components GRIN1, GRIN2A, and GRIN2B cause a myriad of dominant disease phenotypes, with the most common being epilepsy and autism spectrum disorder. Starting from the analysis of a variant of uncertain significance (VUS, GRIN2A G760S), we realized the need for tools to map dominant variants for the components of the NMDA receptor. Some variants within GRIN1, GRIN2A, and GRIN2B exert dominant epilepsy and developmental delay, yet other amino acid variants are conserved and predicted to alter protein function but do not have dominant phenotypes. Common variant annotation tools are not powered to determine pathogenic dominant outcomes. To address this gap, we integrated sequence and structural analyses for GRIN1, GRIN2A, and GRIN2B. Using this approach, we determined that paralog homology mapping and topology can segregate dominant variants, with an elevation of intermolecular contacts between the subunits. Furthermore, demonstrating the general utility of our methodology, we show that 25 VUS within ClinVar also reach a dominant variant annotation, including the GRIN2A G760S variant. Our work suggests paralog homology and protein topology as a powerful strategy within the receptor complex to resolve dominant genetic variants relative to variants that would fit a recessive inheritance, requiring two damaging variants. These strategies should be tested in additional dominant genetic disorders to determine the broader utility.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Vus Of High Impactmentioning

confidence: 99%

N‐methyl‐d‐aspartate (NMDA) receptor genetics: The power of paralog homology and protein dynamics in defining dominant genetic variants

Charron

Hernandez

Bilinovich

et al. 2021

American J of Med Genetics Pt A

Self Cite

View full text Add to dashboard Cite

show abstract

“…Hurdles to AAV gene transfer to airway epithelia for cystic fibrosis include (1) by-passing the mucus to reach the cell surface; (2) binding a receptor at the apical cell surface; (3) endocytosis for cell entry; (4) trafficking to the nucleus; (5) conversion of the single-stranded DNA core to double-stranded DNA followed by concatemerization and/or integration; and (6) achieving therapeutic levels of protein expression. As the current small molecule cystic fibrosis drugs are only recommended for individuals with a delta508 variant, gene therapy is still needed to treat individuals of diverse ancestry not having delta508 [ 82 ]. Over the past decade, improvement in the efficiency of AAV targeting of airway epithelia has been achieved by using different serotypes [ 83 , 84 , 85 , 86 , 87 , 88 ], site-directed mutagenesis modifications of viral capsids [ 89 ], and targeted evolution selection [ 90 , 91 ].…”

Section: Biological Considerationsmentioning

confidence: 99%

Gene Therapy for Genetic Syndromes: Understanding the Current State to Guide Future Care

Henderson,

Zieba,

et al. 2024

BioTech

Self Cite

View full text Add to dashboard Cite

Gene therapy holds promise as a life-changing option for individuals with genetic variants that give rise to disease. FDA-approved gene therapies for Spinal Muscular Atrophy (SMA), cerebral adrenoleukodystrophy, β-Thalassemia, hemophilia A/B, retinal dystrophy, and Duchenne Muscular Dystrophy have generated buzz around the ability to change the course of genetic syndromes. However, this excitement risks over-expansion into areas of genetic disease that may not fit the current state of gene therapy. While in situ (targeted to an area) and ex vivo (removal of cells, delivery, and administration of cells) approaches show promise, they have a limited target ability. Broader in vivo gene therapy trials have shown various continued challenges, including immune response, use of immune suppressants correlating to secondary infections, unknown outcomes of overexpression, and challenges in driving tissue-specific corrections. Viral delivery systems can be associated with adverse outcomes such as hepatotoxicity and lethality if uncontrolled. In some cases, these risks are far outweighed by the potentially lethal syndromes for which these systems are being developed. Therefore, it is critical to evaluate the field of genetic diseases to perform cost–benefit analyses for gene therapy. In this work, we present the current state while setting forth tools and resources to guide informed directions to avoid foreseeable issues in gene therapy that could prevent the field from continued success.

show abstract

Molecular Modeling is an Enabling Approach to Complement and Enhance Channelopathy Research

Zimmermann

2022

Comprehensive Physiology

View full text Add to dashboard Cite

Genomic, transcriptomic, and protein landscape profile of CFTR and cystic fibrosis

Cited by 4 publications

References 78 publications

N‐methyl‐d‐aspartate (NMDA) receptor genetics: The power of paralog homology and protein dynamics in defining dominant genetic variants

N‐methyl‐d‐aspartate (NMDA) receptor genetics: The power of paralog homology and protein dynamics in defining dominant genetic variants

Gene Therapy for Genetic Syndromes: Understanding the Current State to Guide Future Care

Molecular Modeling is an Enabling Approach to Complement and Enhance Channelopathy Research

Contact Info

Product

Resources

About