Back to Search
Start Over
Helicase-inactivating BRIP1 mutation yields Fanconi anemia with microcephaly and other congenital abnormalities.
- Source :
-
Cold Spring Harbor molecular case studies [Cold Spring Harb Mol Case Stud] 2020 Oct 07; Vol. 6 (5). Date of Electronic Publication: 2020 Oct 07 (Print Publication: 2020). - Publication Year :
- 2020
-
Abstract
- Fanconi anemia is a genetically and phenotypically heterogeneous disorder characterized by congenital anomalies, bone marrow failure, cancer, and sensitivity of chromosomes to DNA cross-linking agents. One of the 22 genes responsible for Fanconi anemia is BRIP1 , in which biallelic truncating mutations lead to Fanconi anemia group J and monoallelic truncating mutations predispose to certain cancers. However, of the more than 1000 reported missense mutations in BRIP1 , very few have been functionally characterized. We evaluated the functional consequence of BRIP1 p.R848H (c.2543G > A), which was homozygous in two cousins with low birth weight, microcephaly, upper limb abnormalities, and imperforate anus and for whom chromosome breakage analysis of patient cells revealed increased mitomycin C sensitivity. BRIP1 p.R848H alters a highly conserved residue in the catalytic DNA helicase domain. We show that BRIP1 p.R848H leads to a defect in helicase activity. Heterozygosity at this missense has been reported in multiple cancer patients but, in the absence of functional studies, classified as of unknown significance. Our results support that this mutation is pathogenic for Fanconi anemia in homozygotes and for increased cancer susceptibility in heterozygous carriers.<br /> (© 2020 Kamal et al.; Published by Cold Spring Harbor Laboratory Press.)
- Subjects :
- Alleles
Anus, Imperforate genetics
Anus, Imperforate physiopathology
Child, Preschool
DNA Helicases genetics
DNA-Binding Proteins genetics
Family
Fanconi Anemia Complementation Group Proteins metabolism
Female
Genetic Predisposition to Disease genetics
Humans
Male
Microcephaly genetics
Mutation, Missense genetics
Pedigree
Phenotype
RNA Helicases metabolism
Fanconi Anemia genetics
Fanconi Anemia Complementation Group Proteins genetics
RNA Helicases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2373-2873
- Volume :
- 6
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cold Spring Harbor molecular case studies
- Publication Type :
- Academic Journal
- Accession number :
- 33028645
- Full Text :
- https://doi.org/10.1101/mcs.a005652