Search

Your search keyword '"Koenig, Mary K."' showing total 32 results
Start Over Author "Koenig, Mary K."
32 results on '"Koenig, Mary K."'

3. DNAJC30 defect: a frequent cause of recessive Leber hereditary optic neuropathy and Leigh syndrome

Author

Stenton, Sarah L., primary, Tesarova, Marketa, additional, Sheremet, Natalia L., additional, Catarino, Claudia B., additional, Carelli, Valerio, additional, Ciara, Elżbieta, additional, Curry, Kathryn, additional, Engvall, Martin, additional, Fleming, Leah R., additional, Freisinger, Peter, additional, Iwanicka-Pronicka, Katarzyna, additional, Jurkiewicz, Elżbieta, additional, Klopstock, Thomas, additional, Koenig, Mary K., additional, Kolářová, Hana, additional, Kousal, Bohdan, additional, Krylova, Tatiana, additional, La Morgia, Chiara, additional, Nosková, Lenka, additional, Piekutowska-Abramczuk, Dorota, additional, Russo, Sam N., additional, Stránecký, Viktor, additional, Tóthová, Iveta, additional, Träisk, Frank, additional, and Prokisch, Holger, additional

Published
2022
Full Text
View/download PDF

5. NEXMIF pathogenic variants in individuals of Korean, Vietnamese, and Mexican descent.

Author

Langley, Elizabeth, Farach, Laura S., Koenig, Mary K., Northrup, Hope, Rodriguez‐Buritica, David F., and Mowrey, Kate

Abstract

NEXMIF pathogenic variants have been known to produce a wide spectrum of X‐linked intellectual disability (ID) in both males and females. Thus far, few individuals from diverse populations have been described with NEXMIF‐related disorders. Herein, we report three individuals with NEXMIF pathogenic variants, the first two are the only males of Korean and Vietnamese descent described with this disorder to our knowledge. The last patient is a Hispanic female who harbors the same pathogenic variant as a previously described Caucasian individual, but with differing clinical presentation. These patients present with many classic symptoms of NEXMIF‐related disorders including ID, epilepsy, developmental delay, and dysmorphic features. In addition, they have symptoms that have not been thoroughly described in the literature, including allergies with multiple anaphylactic events and hypothyroidism. This report is intended to raise awareness and educate about the clinical signs that may prompt testing for NEXMIF‐related disorders. [ABSTRACT FROM AUTHOR]

Published
2022
Full Text
View/download PDF

6. De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation

Author

Mao, Dongxue, primary, Reuter, Chloe M., additional, Ruzhnikov, Maura R.Z., additional, Beck, Anita E., additional, Farrow, Emily G., additional, Emrick, Lisa T., additional, Rosenfeld, Jill A., additional, Mackenzie, Katherine M., additional, Robak, Laurie, additional, Wheeler, Matthew T., additional, Burrage, Lindsay C., additional, Jain, Mahim, additional, Liu, Pengfei, additional, Calame, Daniel, additional, Küry, Sébastien, additional, Sillesen, Martin, additional, Schmitz-Abe, Klaus, additional, Tonduti, Davide, additional, Spaccini, Luigina, additional, Iascone, Maria, additional, Genetti, Casie A., additional, Koenig, Mary K., additional, Graf, Madeline, additional, Tran, Alyssa, additional, Alejandro, Mercedes, additional, Lee, Brendan H., additional, Thiffault, Isabelle, additional, Agrawal, Pankaj B., additional, Bernstein, Jonathan A., additional, Bellen, Hugo J., additional, Chao, Hsiao-Tuan, additional, Acosta, Maria T., additional, Adam, Margaret, additional, Adams, David R., additional, Alejandro, Mercedes E., additional, Allard, Patrick, additional, Alvey, Justin, additional, Amendola, Laura, additional, Andrews, Ashley, additional, Ashley, Euan A., additional, Azamian, Mahshid S., additional, Bacino, Carlos A., additional, Bademci, Guney, additional, Baker, Eva, additional, Balasubramanyam, Ashok, additional, Baldridge, Dustin, additional, Bale, Jim, additional, Bamshad, Michael, additional, Barbouth, Deborah, additional, Batzli, Gabriel F., additional, Bayrak-Toydemir, Pinar, additional, Beck, Anita, additional, Beggs, Alan H., additional, Bejerano, Gill, additional, Bennet, Jimmy, additional, Berg-Rood, Beverly, additional, Bernier, Raphael, additional, Berry, Gerard T., additional, Bican, Anna, additional, Bivona, Stephanie, additional, Blue, Elizabeth, additional, Bohnsack, John, additional, Bonnenmann, Carsten, additional, Bonner, Devon, additional, Botto, Lorenzo, additional, Briere, Lauren C., additional, Brokamp, Elly, additional, Burke, Elizabeth A., additional, Butte, Manish J., additional, Byers, Peter, additional, Carey, John, additional, Carrasquillo, Olveen, additional, Chang, Ta Chen Peter, additional, Chanprasert, Sirisak, additional, Clark, Gary D., additional, Coakley, Terra R., additional, Cobban, Laurel A., additional, Cogan, Joy D., additional, Cole, F. Sessions, additional, Colley, Heather A., additional, Cooper, Cynthia M., additional, Cope, Heidi, additional, Craigen, William J., additional, Cunningham, Michael, additional, D’Souza, Precilla, additional, Dai, Hongzheng, additional, Dasari, Surendra, additional, Davids, Mariska, additional, Dayal, Jyoti G., additional, Dell’Angelica, Esteban C., additional, Dhar, Shweta U., additional, Dipple, Katrina, additional, Doherty, Daniel, additional, Dorrani, Naghmeh, additional, Douine, Emilie D., additional, Draper, David D., additional, Duncan, Laura, additional, Earl, Dawn, additional, Eckstein, David J., additional, Eng, Christine M., additional, Esteves, Cecilia, additional, Estwick, Tyra, additional, Fernandez, Liliana, additional, Ferreira, Carlos, additional, Fieg, Elizabeth L., additional, Fisher, Paul G., additional, Fogel, Brent L., additional, Forghani, Irman, additional, Fresard, Laure, additional, Gahl, William A., additional, Glass, Ian, additional, Godfrey, Rena A., additional, Golden-Grant, Katie, additional, Goldman, Alica M., additional, Goldstein, David B., additional, Grajewski, Alana, additional, Groden, Catherine A., additional, Gropman, Andrea L., additional, Hahn, Sihoun, additional, Hamid, Rizwan, additional, Hanchard, Neil A., additional, Hayes, Nichole, additional, High, Frances, additional, Hing, Anne, additional, Hisama, Fuki M., additional, Holm, Ingrid A., additional, Hom, Jason, additional, Horike-Pyne, Martha, additional, Huang, Alden, additional, Huang, Yong, additional, Isasi, Rosario, additional, Jamal, Fariha, additional, Jarvik, Gail P., additional, Jarvik, Jeffrey, additional, Jayadev, Suman, additional, Jiang, Yong-hui, additional, Johnston, Jean M., additional, Karaviti, Lefkothea, additional, Kelley, Emily G., additional, Kiley, Dana, additional, Kohane, Isaac S., additional, Kohler, Jennefer N., additional, Krakow, Deborah, additional, Krasnewich, Donna M., additional, Korrick, Susan, additional, Koziura, Mary, additional, Krier, Joel B., additional, Lalani, Seema R., additional, Lam, Byron, additional, Lam, Christina, additional, Lanpher, Brendan C., additional, Lanza, Ian R., additional, Lau, C. Christopher, additional, LeBlanc, Kimberly, additional, Lee, Hane, additional, Levitt, Roy, additional, Lewis, Richard A., additional, Lincoln, Sharyn A., additional, Liu, Xue Zhong, additional, Longo, Nicola, additional, Loo, Sandra K., additional, Loscalzo, Joseph, additional, Maas, Richard L., additional, Macnamara, Ellen F., additional, MacRae, Calum A., additional, Maduro, Valerie V., additional, Majcherska, Marta M., additional, Malicdan, May Christine V., additional, Mamounas, Laura A., additional, Manolio, Teri A., additional, Mao, Rong, additional, Maravilla, Kenneth, additional, Markello, Thomas C., additional, Marom, Ronit, additional, Marth, Gabor, additional, Martin, Beth A., additional, Martin, Martin G., additional, Martínez-Agosto, Julian A., additional, Marwaha, Shruti, additional, McCauley, Jacob, additional, McConkie-Rosell, Allyn, additional, McCormack, Colleen E., additional, McCray, Alexa T., additional, Mefford, Heather, additional, Merritt, J. Lawrence, additional, Might, Matthew, additional, Mirzaa, Ghayda, additional, Morava-Kozicz, Eva, additional, Moretti, Paolo M., additional, Morimoto, Marie, additional, Mulvihill, John J., additional, Murdock, David R., additional, Nath, Avi, additional, Nelson, Stan F., additional, Newman, John H., additional, Nicholas, Sarah K., additional, Nickerson, Deborah, additional, Novacic, Donna, additional, Oglesbee, Devin, additional, Orengo, James P., additional, Pace, Laura, additional, Pak, Stephen, additional, Pallais, J. Carl, additional, Palmer, Christina G.S., additional, Papp, Jeanette C., additional, Parker, Neil H., additional, Phillips, John A., additional, Posey, Jennifer E., additional, Postlethwait, John H., additional, Potocki, Lorraine, additional, Pusey, Barbara N., additional, Quinlan, Aaron, additional, Raskind, Wendy, additional, Raja, Archana N., additional, Renteria, Genecee, additional, Rives, Lynette, additional, Robertson, Amy K., additional, Rodan, Lance H., additional, Rowley, Robb K., additional, Ruzhnikov, Maura, additional, Sacco, Ralph, additional, Sampson, Jacinda B., additional, Samson, Susan L., additional, Saporta, Mario, additional, Scott, C. Ron, additional, Schaechter, Judy, additional, Schedl, Timothy, additional, Schoch, Kelly, additional, Scott, Daryl A., additional, Shakachite, Lisa, additional, Sharma, Prashant, additional, Shashi, Vandana, additional, Shin, Jimann, additional, Signer, Rebecca, additional, Sillari, Catherine H., additional, Silverman, Edwin K., additional, Sinsheimer, Janet S., additional, Sisco, Kathy, additional, Smith, Kevin S., additional, Solnica-Krezel, Lilianna, additional, Spillmann, Rebecca C., additional, Stoler, Joan M., additional, Stong, Nicholas, additional, Sullivan, Jennifer A., additional, Sun, Angela, additional, Sutton, Shirley, additional, Sweetser, David A., additional, Sybert, Virginia, additional, Tabor, Holly K., additional, Tamburro, Cecelia P., additional, Tan, Queenie K.-G., additional, Tekin, Mustafa, additional, Telischi, Fred, additional, Thorson, Willa, additional, Tifft, Cynthia J., additional, Toro, Camilo, additional, Tran, Alyssa A., additional, Urv, Tiina K., additional, Velinder, Matt, additional, Viskochil, Dave, additional, Vogel, Tiphanie P., additional, Wahl, Colleen E., additional, Wallace, Stephanie, additional, Walley, Nicole M., additional, Walsh, Chris A., additional, Walker, Melissa, additional, Wambach, Jennifer, additional, Wan, Jijun, additional, Wang, Lee-kai, additional, Wangler, Michael F., additional, Ward, Patricia A., additional, Wegner, Daniel, additional, Wener, Mark, additional, Westerfield, Monte, additional, Wise, Anastasia L., additional, Wolfe, Lynne A., additional, Woods, Jeremy D., additional, Yamamoto, Shinya, additional, Yang, John, additional, Yoon, Amanda J., additional, Yu, Guoyun, additional, Zastrow, Diane B., additional, Zhao, Chunli, additional, and Zuchner, Stephan, additional

Published
2020
Full Text
View/download PDF

7. BAZ2B haploinsufficiency as a cause of developmental delay, intellectual disability, and autism spectrum disorder

Author

Scott, Tiana M., primary, Guo, Hui, additional, Eichler, Evan E., additional, Rosenfeld, Jill A., additional, Pang, Kaifang, additional, Liu, Zhandong, additional, Lalani, Seema, additional, Bi, Weimin, additional, Yang, Yaping, additional, Bacino, Carlos A., additional, Streff, Haley, additional, Lewis, Andrea M., additional, Koenig, Mary K., additional, Thiffault, Isabelle, additional, Bellomo, Allison, additional, Everman, David B., additional, Jones, Julie R., additional, Stevenson, Roger E., additional, Bernier, Raphael, additional, Gilissen, Christian, additional, Pfundt, Rolph, additional, Hiatt, Susan M., additional, Cooper, Gregory M., additional, Holder, Jimmy L., additional, and Scott, Daryl A., additional

Published
2020
Full Text
View/download PDF

8. RARS1‐related hypomyelinating leukodystrophy: Expanding the spectrum

Author

Mendes, Marisa I., primary, Green, Lydia M. C., additional, Bertini, Enrico, additional, Tonduti, Davide, additional, Aiello, Chiara, additional, Smith, Desiree, additional, Salsano, Ettore, additional, Beerepoot, Shanice, additional, Hertecant, Jozef, additional, von Spiczak, Sarah, additional, Livingston, John H., additional, Emrick, Lisa, additional, Fraser, Jamie, additional, Russell, Laura, additional, Bernard, Genevieve, additional, Magri, Stefania, additional, Di Bella, Daniela, additional, Taroni, Franco, additional, Koenig, Mary K., additional, Moroni, Isabella, additional, Cappuccio, Gerarda, additional, Brunetti‐Pierri, Nicola, additional, Rhee, Jullie, additional, Mendelsohn, Bryce A., additional, Helbig, Ingo, additional, Helbig, Katherine, additional, Muhle, Hiltrud, additional, Ismayl, Omar, additional, Vanderver, Adeline L., additional, Salomons, Gajja S., additional, van der Knaap, Marjo S., additional, and Wolf, Nicole I., additional

Published
2019
Full Text
View/download PDF

9. Clinical Spectrum and Functional Consequences Associated with Bi-Allelic Pathogenic PNPT1 Variants

Author

Rius, Rocio, primary, Van Bergen, Nicole J., additional, Compton, Alison G., additional, Riley, Lisa G., additional, Kava, Maina P., additional, Balasubramaniam, Shanti, additional, Amor, David J., additional, Fanjul-Fernandez, Miriam, additional, Cowley, Mark J., additional, Fahey, Michael C., additional, Koenig, Mary K., additional, Enns, Gregory M., additional, Sadedin, Simon, additional, Wilson, Meredith J., additional, Tan, Tiong Y., additional, Thorburn, David R., additional, and Christodoulou, John, additional

Published
2019
Full Text
View/download PDF

10. Heterozygous variants in SPTBN1 cause intellectual disability and autism.

Author

Rosenfeld, Jill A., Xiao, Rui, Bekheirnia, Mir Reza, Kanani, Farah, Parker, Michael J., Koenig, Mary K., Haeringen, Arie, Ruivenkamp, Claudia, Rosmaninho‐Salgado, Joana, Almeida, Pedro M., Sá, Joaquim, Pinto Basto, Jorge, Palen, Emily, Oetjens, Kathryn F., Burrage, Lindsay C., Xia, Fan, Liu, Pengfei, Eng, Christine M., Yang, Yaping, and Posey, Jennifer E.

Abstract

Spectrins are common components of cytoskeletons, binding to cytoskeletal elements and the plasma membrane, allowing proper localization of essential membrane proteins, signal transduction, and cellular scaffolding. Spectrins are assembled from α and β subunits, encoded by SPTA1 and SPTAN1 (α) and SPTB, SPTBN1, SPTBN2, SPTBN4, and SPTBN5 (β). Pathogenic variants in various spectrin genes are associated with erythroid cell disorders (SPTA1, SPTB) and neurologic disorders (SPTAN1, SPTBN2, and SPTBN4), but no phenotypes have been definitively associated with variants in SPTBN1 or SPTBN5. Through exome sequencing and case matching, we identified seven unrelated individuals with heterozygous SPTBN1 variants: two with de novo missense variants and five with predicted loss‐of‐function variants (found to be de novo in two, while one was inherited from a mother with a history of learning disabilities). Common features include global developmental delays, intellectual disability, and behavioral disturbances. Autistic features (4/6) and epilepsy (2/7) or abnormal electroencephalogram without overt seizures (1/7) were present in a subset. Identification of loss‐of‐function variants suggests a haploinsufficiency mechanism, but additional functional studies are required to fully elucidate disease pathogenesis. Our findings support the essential roles of SPTBN1 in human neurodevelopment and expand the knowledge of human spectrinopathy disorders. [ABSTRACT FROM AUTHOR]

Published
2021
Full Text
View/download PDF

12. Reanalysis of Clinical Exome Sequencing Data

Author

Liu, Pengfei, primary, Meng, Linyan, additional, Normand, Elizabeth A., additional, Xia, Fan, additional, Song, Xiaofei, additional, Ghazi, Andrew, additional, Rosenfeld, Jill, additional, Magoulas, Pilar L., additional, Braxton, Alicia, additional, Ward, Patricia, additional, Dai, Hongzheng, additional, Yuan, Bo, additional, Bi, Weimin, additional, Xiao, Rui, additional, Wang, Xia, additional, Chiang, Theodore, additional, Vetrini, Francesco, additional, He, Weimin, additional, Cheng, Hanyin, additional, Dong, Jie, additional, Gijavanekar, Charul, additional, Benke, Paul J., additional, Bernstein, Jonathan A., additional, Eble, Tanya, additional, Eroglu, Yasemen, additional, Erwin, Deanna, additional, Escobar, Luis, additional, Gibson, James B., additional, Gripp, Karen, additional, Kleppe, Soledad, additional, Koenig, Mary K., additional, Lewis, Andrea M., additional, Natowicz, Marvin, additional, Mancias, Pedro, additional, Minor, LaKeesha, additional, Scaglia, Fernando, additional, Schaaf, Christian P., additional, Streff, Haley, additional, Vernon, Hilary, additional, Uhles, Crescenda L., additional, Zackai, Elaine H., additional, Wu, Nan, additional, Sutton, V. Reid, additional, Beaudet, Arthur L., additional, Muzny, Donna, additional, Gibbs, Richard A., additional, Posey, Jennifer E., additional, Lalani, Seema, additional, Shaw, Chad, additional, Eng, Christine M., additional, Lupski, James R., additional, and Yang, Yaping, additional

Published
2019
Full Text
View/download PDF

13. A noncommensurate line length modulator

Author

Koenig, Mary K.

Subjects
Modulators (Electronics) -- Design and construction, Microwave devices -- Design and construction, Business, Electronics and electrical industries, Engineering and manufacturing industries, Telecommunications industry, Design and construction
Abstract

A Noncommensurate Line Length Modulator Introduction There are many electronic applications that require amplitude modulation. Automatic leveling control loops and fast pulse modulation incorporate shunt PIN diodes to realize circuits [...]

Published
1991

14. RARS1‐related hypomyelinating leukodystrophy: Expanding the spectrum.

Author

Mendes, Marisa I., Green, Lydia M. C., Bertini, Enrico, Tonduti, Davide, Aiello, Chiara, Smith, Desiree, Salsano, Ettore, Beerepoot, Shanice, Hertecant, Jozef, Spiczak, Sarah, Livingston, John H., Emrick, Lisa, Fraser, Jamie, Russell, Laura, Bernard, Genevieve, Magri, Stefania, Di Bella, Daniela, Taroni, Franco, Koenig, Mary K., and Moroni, Isabella

Subjects
LEUKODYSTROPHY, CEREBRAL atrophy, COGNITION disorders, NUCLEOTIDE sequencing, AMINO acids, WESTERN immunoblotting
Abstract

Objective: Biallelic variants in RARS1, encoding the cytoplasmic tRNA synthetase for arginine (ArgRS), cause a hypomyelinating leukodystrophy. This study aimed to investigate clinical, neuroradiological and genetic features of patients with RARS1‐related disease, and to identify possible genotype‐phenotype relationships. Methods: We performed a multinational cross‐sectional survey among 20 patients with biallelic RARS1 variants identified by next‐generation sequencing techniques. Clinical data, brain MRI findings and genetic results were analyzed. Additionally, ArgRS activity was measured in fibroblasts of four patients, and translation of long and short ArgRS isoforms was quantified by western blot. Results: Clinical presentation ranged from severe (onset in the first 3 months, usually with refractory epilepsy and early brain atrophy), to intermediate (onset in the first year with nystagmus and spasticity), and mild (onset around or after 12 months with minimal cognitive impairment and preserved independent walking). The most frequent RARS1 variant, c.5A>G, led to mild or intermediate phenotypes, whereas truncating variants and variants affecting amino acids close to the ArgRS active centre led to severe phenotypes. ArgRS activity was significantly reduced in three patients with intermediate and severe phenotypes; in a fourth patient with intermediate to severe presentation, we measured normal ArgRS activity, but found translation mainly of the short instead of the long ArgRS isoform. Interpretation: Variants in RARS1 impair ArgRS activity and do not only lead to a classic hypomyelination presentation with nystagmus and spasticity, but to a wide spectrum, ranging from severe, early‐onset epileptic encephalopathy with brain atrophy to mild disease with relatively preserved myelination. [ABSTRACT FROM AUTHOR]

Published
2020
Full Text
View/download PDF

15. Idiopathic Central Nervous System Inflammatory Disease in the Setting of HLA-B27 Uveitis.

Author

Crowell, Eric L., Pfeiffer, Margaret L., Kamdar, Ankur A., Koenig, Mary K., Wittenberg, Susan E., Supsupin, Emilio P., and Adesina, Ore-ofe O.

Subjects
IRIDOCYCLITIS, CENTRAL nervous system diseases, HLA histocompatibility antigens, SUPERIOR colliculus, CEREBROSPINAL fluid, UVEITIS
Abstract

Purpose: The purpose of the article is to describe a novel case of idiopathic central nervous system inflammatory disease with bilateral human leukocyte antigen (HLA)-B27-positive anterior uveitis. Methods/Results: A 15-year-old African American boy with bilateral HLA-B27-positive anterior uveitis controlled with topical and oral steroids for 8 months acutely developed headaches, left eyelid ptosis, and binocular diplopia. Imaging showed lesions in the right midbrain, superior colliculus, cerebellar peduncles, and cerebellar vermis and leptomeningeal enhancement along the vermian foliae. Cerebral spinal fluid tests showed mild lymphohistiocytic pleocytosis with negative cytology; inflammatory and infectious workup were negative. He received intravenous methylprednisolone without initial symptomatic improvement; repeat magnetic resonance imaging (MRI) showed reduced lesion burden. Oral steroids were continued; his symptoms resolved in 1 month. Repeat MRI 2 months after presentation showed almost complete lesion resolution. Conclusions: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) was diagnosed. HLA-B27 positivity may represent a novel association with CLIPPERS. [ABSTRACT FROM AUTHOR]

Published
2019
Full Text
View/download PDF

18. A high-speed microwave pulse modulator

Author

Koenig, Mary K.

Subjects
Pulse Amplitude Modulation, Circuit Design, System Design, Performance, Add-In/On Devices, Hewlett-Packard Co. -- Product information, HP 8360 (Oscillator) -- Equipment and supplies
Abstract

This optional fast pulse modulator uses an unequally spaced diode topology to achieve a wide bandwidth and a high on-off ratio without resorting to performance-limiting diode saturation. FAST PULSE MODULATION, […]

Published
1991

19. Solid organ transplantation in primary mitochondrial disease: Proceed with caution

Author

Parikh, Sumit, primary, Karaa, Amel, additional, Goldstein, Amy, additional, Ng, Yi S., additional, Gorman, Grainne, additional, Feigenbaum, Annette, additional, Christodoulou, John, additional, Haas, Richard, additional, Tarnopolsky, Mark, additional, Cohen, Bruce K., additional, Dimmock, David, additional, Feyma, Tim, additional, Koenig, Mary K., additional, Mundy, Helen, additional, Niyazov, Dmitriy, additional, Saneto, Russell P., additional, Wainwright, Mark S., additional, Wusthoff, Courtney, additional, McFarland, Robert, additional, and Scaglia, Fernando, additional

Published
2016
Full Text
View/download PDF

28. Low-voltage electro-optic polymer modulators

Author

Dinu, Raluca, primary, Jin, Danliang, additional, Huang, Diyun, additional, Koenig, Mary K., additional, Barklund, Anna M., additional, Fang, Yun, additional, Parker, Timothy C., additional, Shi, Zhengwei, additional, Luo, Jingdong, additional, and Jen, Alex K-Y., additional

Published
2006
Full Text
View/download PDF

32. Missense variants in the middle domain of DNM1L in cases of infantile encephalopathy alter peroxisomes and mitochondria when assayed in Drosophila.

Author

Chao YH, Robak LA, Xia F, Koenig MK, Adesina A, Bacino CA, Scaglia F, Bellen HJ, and Wangler MF

Subjects
Amino Acid Sequence, Animals, Cytoskeletal Proteins metabolism, Drosophila melanogaster genetics, Drosophila melanogaster metabolism, Dynamins, Exome genetics, Female, GTP-Binding Proteins metabolism, Humans, Infant, Infant, Newborn, Male, Mitochondria genetics, Mitochondria metabolism, Pedigree, Peroxisomes genetics, Peroxisomes metabolism, Phenotype, Protein Domains, Sequence Homology, Amino Acid, Spasms, Infantile pathology, Drosophila melanogaster growth & development, GTP Phosphohydrolases genetics, Microtubule-Associated Proteins genetics, Mitochondria pathology, Mitochondrial Proteins genetics, Mutation, Missense genetics, Peroxisomes pathology, Spasms, Infantile genetics
Abstract

Defects in organelle dynamics underlie a number of human degenerative disorders, and whole exome sequencing (WES) is a powerful tool for studying genetic changes that affect the cellular machinery. WES may uncover variants of unknown significance (VUS) that require functional validation. Previously, a pathogenic de novo variant in the middle domain of DNM1L (p.A395D) was identified in a single patient with a lethal defect of mitochondrial and peroxisomal fission. We identified two additional patients with infantile encephalopathy and partially overlapping clinical features, each with a novel VUS in the middle domain of DNM1L (p.G350R and p.E379K). To evaluate pathogenicity, we generated transgenic Drosophila expressing wild-type or variant DNM1L. We find that human wild-type DNM1L rescues the lethality as well as specific phenotypes associated with the loss of Drp1 in Drosophila. Neither the p.A395D variant nor the novel variant p.G350R rescue lethality or other phenotypes. Moreover, overexpression of p.A395D and p.G350R in Drosophila neurons, salivary gland and muscle strikingly altered peroxisomal and mitochondrial morphology. In contrast, the other novel variant (p.E379K) rescued lethality and did not affect organelle morphology, although it was associated with a subtle mitochondrial trafficking defect in an in vivo assay. Interestingly, the patient with the p.E379K variant also has a de novo VUS in pyruvate dehydrogenase 1 (PDHA1) affecting the same amino acid (G150) as another case of PDHA1 deficiency suggesting the PDHA1 variant may be pathogenic. In summary, detailed clinical evaluation and WES with functional studies in Drosophila can distinguish different functional consequences of newly-described DNM1L alleles., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Published
2016
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results