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[A novel Krit-1 mutation in Han family with cerebral cavernous malformation]
Yu-lun Xu1, Ji-zong Zhao, Bing-quan Wu
1Department of Neurosurgery, Tiantan Hospital Affiliated to Capital University of Medical Sciences, Beijing 100050, China.
Insights
Researchers identified a new Krit-1 gene mutation causing familial cerebral cavernous malformation (CCM) in a Han Chinese family. This discovery enables early molecular diagnosis for this neurological disorder.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Familial cerebral cavernous malformation (CCM) is a genetic disorder.
- Mutations in the Krit-1 gene are associated with CCM.
- Understanding genetic causes is crucial for diagnosis and treatment.
Purpose of the Study:
- To detect mutations in the Krit-1 gene responsible for familial cerebral cavernous malformation (CCM).
- To investigate the Han ethnic population in Asia.
- To identify novel mutations for improved diagnostics.
Main Methods:
- Screening of Krit-1 gene in two CCM families and eight sporadic individuals.
- Utilizing Polymerase Chain Reaction (PCR) amplification of 16 exons.
- Employing direct sequencing for mutation detection.
Main Results:
- A novel nonsense point mutation (S430X) was identified in exon 14 of the Krit-1 gene in family A.
- This mutation predicts a premature termination codon, leading to a truncated KRIT1 protein.
- No mutations were found in sporadic individuals, except for a single nucleotide polymorphism.
Conclusions:
- This study reports the first family in the Han population in Asia with CCM and a novel mutation in the CCM1 gene.
- The identified mutation results in a truncated KRIT1 protein, impacting its function.
- This finding facilitates efficient presymptomatic molecular diagnosis of CCM.
Objective:
To detect the mutations of Krit-1 gene that cause familial cerebral cavernous malformation (CCM) in the Han ethnic origin.
Methods:
The subjects were hospitalized in the Department of Neurosurgery, Tiantan Hospital affiliated to Capital University of Medical Sciences. Two families (A and B) and 8 apparently sporadic individuals affected with CCM were screened for mutations of Krit-1 gene. Members of the family CCM have a wide range in age of onset with seizures, headaches and skin lesions. The gene was screened by PCR amplification of 16 exons and mutation was detected by direct sequencing.
Results:
In family A samples, analysis of the Krit-1 gene revealed a new point mutation in exon 14 [a heterozygous C to G transition at nucleotide 1 289 (counting from the start codon or nt 2 308 counting from the first nt of the mRNA, aligned according to Gene Bank AF388384)] which predicts the substitution of a premature termination codon for Serine at codon 430 (S430X), belonging a nonsense point mutation. No mutation was identified in one of family A members as well as in any of the sporadic individuals with the exception of a single nucleotide polymorphism.
Conclusions:
Report the first family in the Han with CCM having a novel mutation in the CCM1 gene on the continent of Asia. The newly identified mutation creates a premature termination codon and is predicted to produce a truncated Krev1 interaction-trapped 1 protein, KRIT1. This result allows efficient presymptomatic molecular diagnosis.