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Browsing by Author "McPheron, Molly"
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Item HNRNPC haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder(Elsevier, 2023) Niggl, Eva; Bouman, Arjan; Briere, Lauren C.; Hoogenboezem, Remco M.; Wallaard, Ilse; Park, Joohyun; Admard, Jakob; Wilke, Martina; Harris-Mostert, Emilio D. R. O.; Elgersma, Minetta; Bain, Jennifer; Balasubramanian, Meena; Banka, Siddharth; Benke, Paul J.; Bertrand, Miriam; Blesson, Alyssa E.; Clayton-Smith, Jill; Ellingford, Jamie M.; Gillentine, Madelyn A.; Goodloe, Dana H.; Haack, Tobias B.; Jain, Mahim; Krantz, Ian; Luu, Sharon M.; McPheron, Molly; Muss, Candace L.; Raible, Sarah E.; Robin, Nathaniel H.; Spiller, Michael; Starling, Susan; Sweetser, David A.; Thiffault, Isabelle; Vetrini, Francesco; Witt, Dennis; Woods, Emily; Zhou, Dihong; Genomics England Research Consortium; Undiagnosed Diseases Network; Elgersma, Ype; van Esbroeck, Annelot C. M.; Medical and Molecular Genetics, School of MedicineHeterogeneous nuclear ribonucleoprotein C (HNRNPC) is an essential, ubiquitously abundant protein involved in mRNA processing. Genetic variants in other members of the HNRNP family have been associated with neurodevelopmental disorders. Here, we describe 13 individuals with global developmental delay, intellectual disability, behavioral abnormalities, and subtle facial dysmorphology with heterozygous HNRNPC germline variants. Five of them bear an identical in-frame deletion of nine amino acids in the extreme C terminus. To study the effect of this recurrent variant as well as HNRNPC haploinsufficiency, we used induced pluripotent stem cells (iPSCs) and fibroblasts obtained from affected individuals. While protein localization and oligomerization were unaffected by the recurrent C-terminal deletion variant, total HNRNPC levels were decreased. Previously, reduced HNRNPC levels have been associated with changes in alternative splicing. Therefore, we performed a meta-analysis on published RNA-seq datasets of three different cell lines to identify a ubiquitous HNRNPC-dependent signature of alternative spliced exons. The identified signature was not only confirmed in fibroblasts obtained from an affected individual but also showed a significant enrichment for genes associated with intellectual disability. Hence, we assessed the effect of decreased and increased levels of HNRNPC on neuronal arborization and neuronal migration and found that either condition affects neuronal function. Taken together, our data indicate that HNRNPC haploinsufficiency affects alternative splicing of multiple intellectual disability-associated genes and that the developing brain is sensitive to aberrant levels of HNRNPC. Hence, our data strongly support the inclusion of HNRNPC to the family of HNRNP-related neurodevelopmental disorders.Item Relationship satisfaction in adults with phenylketonuria is positively associated with following recommended treatment, having a partner involved in management, and maintaining good health(Springer, 2023) Sundstrom, Rachel; Wetherill, Leah; Sapp, Katie; McPheron, Molly; Lah, Melissa; Medical and Molecular Genetics, School of MedicineRationale: Phenylketonuria (PKU) is a metabolic condition that requires treatment for life. There is increasing evidence that chronic illnesses put strain on relationships and marriages. However, no studies have examined the unique factors that metabolic conditions have on affected individuals and their relationship satisfaction. We surveyed a population of adult patients with PKU and assessed how management, treatment, and lifestyle factors impact their relationship satisfaction. Purpose: The purpose of our study was to explore whether factors such as involvement of partner in PKU management, impact of challenges unique to PKU (e.g., diet, family planning, mood disturbances), and PKU treatment types were associated with the degree of relationship satisfaction. Method: We surveyed adult patients with PKU (n = 82) who were either currently in or had previously been in a long-term relationship. We developed a 78-question survey that included unique questions regarding lifestyle, treatment, and management of their PKU in addition to a validated Relationship Assessment Score. Questions included single choice, multiple choice, and 3 open-ended questions. Results: We found that higher relationship satisfaction was associated with increased partner involvement, increased health, and adherence to recommended PKU treatments. Participants utilizing both diet and pharmaceutical treatment had the highest relationship satisfaction. Finally, participants who reported that their PKU did not contribute to the ending of a previous relationship reported higher relationship satisfaction scores. Conclusion: This study suggests that involvement of partners in the management and treatment of a chronic illness and adherence to recommended treatments can significantly improve relationship satisfaction.