PUBLICATION
Novel loss-of-function variants expand ABCC9-related intellectual disability and myopathy syndrome
- Authors
- Efthymiou, S., Scala, M., Nagaraj, V., Ochenkowska, K., Komdeur, F.L., Liang, R.A., Abdel-Hamid, M.S., Sultan, T., Barøy, T., Van Ghelue, M., Vona, B., Maroofian, R., Zafar, F., Alkuraya, F.S., Zaki, M.S., Severino, M., Duru, K.C., Tryon, R.C., Brauteset, L.V., Ansari, M., Hamilton, M., van Haelst, M.M., van Haaften, G., Zara, F., Houlden, H., Samarut, É., Nichols, C.G., Smeland, M.F., McClenaghan, C.
- ID
- ZDB-PUB-240115-3
- Date
- 2024
- Source
- Brain : a journal of neurology 147(5): 1822-1836 (Journal)
- Registered Authors
- Nichols, Colin G., Samarut, Eric, Tryon, Robert
- Keywords
- ABCC9, KATP channels, SUR2, neurodevelopmental disorder
- MeSH Terms
-
- Adolescent
- Adult
- Animals
- Child
- Child, Preschool
- Female
- Humans
- Intellectual Disability*/genetics
- Loss of Function Mutation/genetics
- Male
- Muscular Diseases*/genetics
- Pedigree
- Sulfonylurea Receptors*/genetics
- Young Adult
- Zebrafish
- PubMed
- 38217872 Full text @ Brain
Citation
Efthymiou, S., Scala, M., Nagaraj, V., Ochenkowska, K., Komdeur, F.L., Liang, R.A., Abdel-Hamid, M.S., Sultan, T., Barøy, T., Van Ghelue, M., Vona, B., Maroofian, R., Zafar, F., Alkuraya, F.S., Zaki, M.S., Severino, M., Duru, K.C., Tryon, R.C., Brauteset, L.V., Ansari, M., Hamilton, M., van Haelst, M.M., van Haaften, G., Zara, F., Houlden, H., Samarut, É., Nichols, C.G., Smeland, M.F., McClenaghan, C. (2024) Novel loss-of-function variants expand ABCC9-related intellectual disability and myopathy syndrome. Brain : a journal of neurology. 147(5):1822-1836.
Abstract
Loss-of-function mutation of ABCC9, the gene encoding the SUR2 subunit of ATP sensitive-potassium (KATP) channels, was recently associated with autosomal recessive ABCC9-related intellectual disability and myopathy syndrome (AIMS). Here we identify nine additional subjects, from seven unrelated families, harboring different homozygous LoF variants in ABCC9 and presenting with a conserved range of clinical features. All variants are predicted to result in severe truncations or in-frame deletions within SUR2, leading to the generation of non-functional SUR2-dependent KATP channels. Affected individuals show psychomotor delay and intellectual disability of variable severity, microcephaly, corpus callosum and white matter abnormalities, seizures, spasticity, short stature, muscle fatigability, and weakness. Heterozygous parents do not show any conserved clinical pathology but report multiple incidences of intrauterine fetal death, which were also observed in an eighth family included in this study. In vivo studies of abcc9 LoF in zebrafish revealed an exacerbated motor response to pentylenetetrazole, a pro-convulsive drug, consistent with impaired neurodevelopment associated with an increased seizure susceptibility. Our findings define an ABCC9 LoF related phenotype, expanding the genotypic and phenotypic spectrum of AIMS and reveal novel human pathologies arising from KATP channel dysfunction.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping