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Variable expression of cerebral cavernous malformations in carriers of a premature termination codon in exon 17 of the Krit1 gene.

Lucas M, Costa AF, García-Moreno JM, Solano F, Gamero MA, Izquierdo G - BMC Neurol (2003)

Bottom Line: Patients in this family, harbouring the same mutation, illustrate the very variable clinical and radiological expression of a Krit1 mutation.The early and critical onset in the proband contrasts with minor clinical findings in affected relatives.This consideration is important in genetic counselling.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Biology Services of the Virgen Macarena University Hospital, Avda Dr, Fedriani sn, 41009 Sevilla, Spain. lucas@us.es

ABSTRACT

Background: Cerebral cavernous malformations (CCM) present as either sporadic or autosomal dominant conditions with incomplete penetrance of symptoms. Differences in genetic and environmental factors might be minimized among first-degree relatives. We therefore studied clinical expression in a family with several affected members.

Methods: We studied a three-generation family with the onset of CCM as a cerebral haemorrhage in the younger (four-year-old) sibling. Identification and enumeration of CCMs were performed in T2-weighted or gradient-echo MRIs of the whole brains. Genetic analysis comprised SCCP, sequencing and restriction polymorphism of the Krit1 gene in the proband and at risk relatives.

Results: The phenotypes of cerebral cavernous malformations (CCMs) in carriers of Krit1 mutations were very variable. We identified a novel frameshift mutation caused by a 1902A insertion in exon 17 of the Krit1 gene, which leads to a premature TAA triplet and predicts the truncating phenotype Y634X. A very striking finding was the absence of both clinical symptoms and CCMs in the eldest sibling harbouring the 1902insA.

Conclusions: Patients in this family, harbouring the same mutation, illustrate the very variable clinical and radiological expression of a Krit1 mutation. The early and critical onset in the proband contrasts with minor clinical findings in affected relatives. This consideration is important in genetic counselling.

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Related in: MedlinePlus

Left panel, SCCP of the proband and parents of CVE10 PCR was performed with the reaction mixture supplemented with [α32P]-dCTP. Aliquots of the product were run in acrylamide gels (see Methods) and revealed by auto-radiography. Right panel, chromatogram of the 1902InsA. Traces of the sense (upper) and antisense (lower) DNA strands of the proband. The wild type and mutated nucleotide sequences and the aminoacid change are indicated over the sense strand. The sequence shows the site of the 1902insA mutation (see arrow) and the frameshift. The ambiguities are caused by the overlapping bands of the wild type and mutated strands due to the nucleotide insertion. The stop TAA triplet predicts a truncating protein with the changed phenotype Y634X.
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Figure 2: Left panel, SCCP of the proband and parents of CVE10 PCR was performed with the reaction mixture supplemented with [α32P]-dCTP. Aliquots of the product were run in acrylamide gels (see Methods) and revealed by auto-radiography. Right panel, chromatogram of the 1902InsA. Traces of the sense (upper) and antisense (lower) DNA strands of the proband. The wild type and mutated nucleotide sequences and the aminoacid change are indicated over the sense strand. The sequence shows the site of the 1902insA mutation (see arrow) and the frameshift. The ambiguities are caused by the overlapping bands of the wild type and mutated strands due to the nucleotide insertion. The stop TAA triplet predicts a truncating protein with the changed phenotype Y634X.


Variable expression of cerebral cavernous malformations in carriers of a premature termination codon in exon 17 of the Krit1 gene.

Lucas M, Costa AF, García-Moreno JM, Solano F, Gamero MA, Izquierdo G - BMC Neurol (2003)

Left panel, SCCP of the proband and parents of CVE10 PCR was performed with the reaction mixture supplemented with [α32P]-dCTP. Aliquots of the product were run in acrylamide gels (see Methods) and revealed by auto-radiography. Right panel, chromatogram of the 1902InsA. Traces of the sense (upper) and antisense (lower) DNA strands of the proband. The wild type and mutated nucleotide sequences and the aminoacid change are indicated over the sense strand. The sequence shows the site of the 1902insA mutation (see arrow) and the frameshift. The ambiguities are caused by the overlapping bands of the wild type and mutated strands due to the nucleotide insertion. The stop TAA triplet predicts a truncating protein with the changed phenotype Y634X.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC184376&req=5

Figure 2: Left panel, SCCP of the proband and parents of CVE10 PCR was performed with the reaction mixture supplemented with [α32P]-dCTP. Aliquots of the product were run in acrylamide gels (see Methods) and revealed by auto-radiography. Right panel, chromatogram of the 1902InsA. Traces of the sense (upper) and antisense (lower) DNA strands of the proband. The wild type and mutated nucleotide sequences and the aminoacid change are indicated over the sense strand. The sequence shows the site of the 1902insA mutation (see arrow) and the frameshift. The ambiguities are caused by the overlapping bands of the wild type and mutated strands due to the nucleotide insertion. The stop TAA triplet predicts a truncating protein with the changed phenotype Y634X.
Bottom Line: Patients in this family, harbouring the same mutation, illustrate the very variable clinical and radiological expression of a Krit1 mutation.The early and critical onset in the proband contrasts with minor clinical findings in affected relatives.This consideration is important in genetic counselling.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Biology Services of the Virgen Macarena University Hospital, Avda Dr, Fedriani sn, 41009 Sevilla, Spain. lucas@us.es

ABSTRACT

Background: Cerebral cavernous malformations (CCM) present as either sporadic or autosomal dominant conditions with incomplete penetrance of symptoms. Differences in genetic and environmental factors might be minimized among first-degree relatives. We therefore studied clinical expression in a family with several affected members.

Methods: We studied a three-generation family with the onset of CCM as a cerebral haemorrhage in the younger (four-year-old) sibling. Identification and enumeration of CCMs were performed in T2-weighted or gradient-echo MRIs of the whole brains. Genetic analysis comprised SCCP, sequencing and restriction polymorphism of the Krit1 gene in the proband and at risk relatives.

Results: The phenotypes of cerebral cavernous malformations (CCMs) in carriers of Krit1 mutations were very variable. We identified a novel frameshift mutation caused by a 1902A insertion in exon 17 of the Krit1 gene, which leads to a premature TAA triplet and predicts the truncating phenotype Y634X. A very striking finding was the absence of both clinical symptoms and CCMs in the eldest sibling harbouring the 1902insA.

Conclusions: Patients in this family, harbouring the same mutation, illustrate the very variable clinical and radiological expression of a Krit1 mutation. The early and critical onset in the proband contrasts with minor clinical findings in affected relatives. This consideration is important in genetic counselling.

Show MeSH
Related in: MedlinePlus