De Novo Variants Disrupting the HX Repeat Motif of ATN1 Cause a Recognizable Non-Progressive Neurocognitive Syndrome
| Autor: | Tejaswi Kandula, Maria J. Guillen Sacoto, Mais Hashem, Saima Kayani, André E. Minoche, Edwin P. Kirk, Łukasz Jaremko, Heba M. Jalal Ahmed, Marwan Shinawi, Elizabeth E. Palmer, Christel Thauvin, Molly Snyder, Mark J. Cowley, Muddathir H Hamad, Maria Mercedes Villanueva, Seungbeom Hong, Fatema Al Zahrani, Laurence Faivre, Suliat F. Yakubu, Ann M. E. Bye, Velimir Gayevskiy, Megan T. Cho, Jasmeen S. Merzaban, Marisa V. Andrews, Alexander P. Drew, Ruth E. Bristol, Jill A. Rosenfeld, Stefan T. Arold, Lindsay B. Henderson, Antonio Vitobello, Tony Roscioli, Clare Puttick, Mariusz Jaremko, Rui Xiao, Fajr A. Aleisa, Amber Begtrup, Marilyn C. Jones, Fowzan S. Alkuraya, Rebecca Macintosh, Marcel E. Dinger, Kristin Lindstrom, Rani Sachdev, Angeles Schteinschnaider |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male allelic disorders Amino Acid Motifs Neurodegenerative Medical and Health Sciences Repetitive Sequences Epilepsy Motif (narrative) 0302 clinical medicine Missense mutation 2.1 Biological and endogenous factors Aetiology Child Genetics (clinical) Genetics Pediatric Genetics & Heredity Neurodegeneration Syndrome Biological Sciences Prognosis Phenotype Hypotonia developmental delay intellectual disability Child Preschool symbols Female dysmorphic medicine.symptom Neurocognitive Disorders Nerve Tissue Proteins Biology 03 medical and health sciences symbols.namesake Atrophy Rare Diseases Report medicine Humans Preschool Repetitive Sequences Nucleic Acid Nucleic Acid business.industry Neurosciences Correction Infant Genetic Variation medicine.disease Human genetics HX repeat Brain Disorders 030104 developmental biology Mendelian inheritance Human genome business Neurocognitive 030217 neurology & neurosurgery |
| Zdroj: | American journal of human genetics, vol 104, iss 3 |
| Popis: | Polyglutamine expansions in the transcriptional co-repressor Atrophin-1, encoded by ATN1, cause the neurodegenerative condition dentatorubral-pallidoluysian atrophy (DRPLA) via a proposed novel toxic gain of function. We present detailed phenotypic information on eight unrelated individuals who have de novo missense and insertion variants within a conserved 16-amino-acid "HX repeat" motif of ATN1. Each of the affected individuals has severe cognitive impairment and hypotonia, a recognizable facial gestalt, and variable congenital anomalies. However, they lack the progressive symptoms typical of DRPLA neurodegeneration. To distinguish this subset of affected individuals from the DRPLA diagnosis, we suggest using the term CHEDDA (congenital hypotonia, epilepsy, developmental delay, digit abnormalities) to classify the condition. CHEDDA-related variants alter the particular structural features of the HX repeat motif, suggesting that CHEDDA results from perturbation of the structural and functional integrity of the HX repeat. We found several non-homologous human genes containing similar motifs of eight to 10 HX repeat sequences, including RERE, where disruptive variants in this motif have also been linked to a separate condition that causes neurocognitive and congenital anomalies. These findings suggest that perturbation of the HX motif might explain other Mendelian human conditions. |
| Databáze: | OpenAIRE |
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