Koko, Mahmoud ORCID: 0000-0001-9512-0184, Yahia, Ashraf, Elsayed, Liena E., Hamed, Ahlam A., Mohammed, Inaam N., Elseed, Maha A., Hamad, Muddathir H. A., Babai, Arwa M., Siddig, Rayan A., Abd Allah, Amal S. I., Mohamed, Mayada, EL-Amin, Melka, Esteves, Typhaine, Altmuller, Janine, Toliat, Mohammad Reza, Thiele, Holger, Nurnberg, Peter, Salih, Mustafa A., Ahmed, Ammar E., Lerche, Holger and Stevanin, Giovanni ORCID: 0000-0001-9368-8657 (2021). An identical-by-descent novel splice-donor variant in PRUNE1 causes a neurodevelopmental syndrome with prominent dystonia in two consanguineous Sudanese families. Ann. Hum. Genet., 85 (5). S. 186 - 196. HOBOKEN: WILEY. ISSN 1469-1809

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Abstract

PRUNE1 is linked to a wide range of neurodevelopmental and neurodegenerative phenotypes. Multiple pathogenic missense and stop-gain PRUNE1 variants were identified in its DHH and DHHA2 phosphodiesterase domains. Conversely, a single splice alteration was previously reported. We investigated five patients from two unrelated consanguineous Sudanese families with an inherited severe neurodevelopmental disorder using whole-exome sequencing coupled with homozygosity mapping, segregation, and haplotype analysis. We identified a founder haplotype transmitting a homozygous canonical splice-donor variant (NM_021222.3:c.132+2T > C) in intron 2 of PRUNE1 segregated with the phenotype in all the patients. This splice variant possibly results in an in-frame deletion in the DHH domain or premature truncation of the protein. The phenotypes of the affected individuals showed phenotypic similarities characterized by remarkable pyramidal dysfunction and prominent extrapyramidal features (severe dystonia and bradykinesia). In conclusion, we identified a novel founder variant in PRUNE1 and corroborated abnormal splicing events as a disease mechanism in PRUNE1-related disorders. Given the phenotypes' consistency coupled with the founder effect, canonical and cryptic PRUNE1 splice-site variants should be carefully evaluated in patients presenting with prominent dystonia and pyramidal dysfunction.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Koko, MahmoudUNSPECIFIEDorcid.org/0000-0001-9512-0184UNSPECIFIED
Yahia, AshrafUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Elsayed, Liena E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hamed, Ahlam A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mohammed, Inaam N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Elseed, Maha A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hamad, Muddathir H. A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Babai, Arwa M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Siddig, Rayan A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abd Allah, Amal S. I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mohamed, MayadaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
EL-Amin, MelkaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Esteves, TyphaineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmuller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toliat, Mohammad RezaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nurnberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Salih, Mustafa A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ahmed, Ammar E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lerche, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stevanin, GiovanniUNSPECIFIEDorcid.org/0000-0001-9368-8657UNSPECIFIED
URN: urn:nbn:de:hbz:38-601080
DOI: 10.1111/ahg.12437
Journal or Publication Title: Ann. Hum. Genet.
Volume: 85
Number: 5
Page Range: S. 186 - 196
Date: 2021
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1469-1809
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SITE MUTATION; GENE; NM23-H1; DISEASEMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60108

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