Mutation screening at the RNA level of the STK11/LKB1 gene in Peutz‐Jeghers syndrome reveals complex splicing abnormalities and a novel mRNA isoform (STK11 c.597⁁598insIVS4)

@article{Abed2001MutationSA,
  title={Mutation screening at the RNA level of the STK11/LKB1 gene in Peutz‐Jeghers syndrome reveals complex splicing abnormalities and a novel mRNA isoform (STK11 c.597⁁598insIVS4)},
  author={Abdalla A. Abed and Klaus G{\"u}nther and Cornelia Kraus and Werner M Hohenberger and Wolfgang G. Ballhausen},
  journal={Human Mutation},
  year={2001},
  volume={18}
}
This study was intended to evaluate a diagnostic reverse transcriptase polymerase chain reaction based protein‐truncation test for the identification of germline mutations in the serine/threonine protein kinase 11 (STK11, also designated LKB1) gene in Peutz‐Jeghers syndrome (PJS). Our data exemplify that the inactivation of STK11 can be due to unusual disturbances in splicing regulation which result in truncations of the protein. However, nonsense mediated mRNA decay must be blocked with… 

Implications of Splicing Alterations in the Onset and Phenotypic Variability of a Family with Subclinical Manifestation of Peutz–Jeghers Syndrome: Bioinformatic and Molecular Evidence

The results have led the hypothesis that the c.465-51 T>C intronic variant, which segregates with the wild type allele, could increase the splicing effectiveness of STK11 wild-type allele and compensate the side effect of thec.597 G>A splicing mutation, being responsible for the phenotypic variability observed within this family.

LKB1 exonic and whole gene deletions are a common cause of Peutz-Jeghers syndrome

These results lessen the possibility of a second PJS locus, as the detection rate of germline mutations in PJS patients was about 80% (59/76), and it is suggested that MLPA, or a suitable alternative, should be used for routine genetic testing of P JS patients in clinical practice.

Mutations in the human LKB1/STK11 gene

A review of the literature provides a total of 40 different somatic LKB1 mutations in 41 sporadic tumors and seven cancer cell lines, which are concordant with the germline mutation spectrum.

Autoimmune regulator-1 messenger ribonucleic acid analysis in a novel intronic mutation and two additional novel AIRE gene mutations in a cohort of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients.

For the first time, a novel intronic mutation was investigated on the mRNA level in APECED, which could be particularly important for APECed patients where no or only heterozygous mutation on the genomic DNA level is detected.

RNA‐based mutation analysis identifies an unusual MSH6 splicing defect and circumvents PMS2 pseudogene interference

Using this assay, which is based on direct cDNA sequencing of RT‐PCR products, two families with children suspected to suffer from MMR‐D syndrome are investigated and it is demonstrated that RNA‐based PMS2 testing effectively avoids the caveats of genomic DNA amplification approaches, and will allow more sensitive mutation analysis in MMR deficiency and in HNPCC patients withPMS2 defects.

Characterization of the STK11 splicing variant as a normal splicing isomer in a patient with Peutz–Jeghers syndrome harboring genomic deletion of the STK11 gene

It is concluded that the splicing variant detected in a Peutz–Jeghers syndrome patient harboring a genomic deletion in the vicinity of exon 1 of the STK11 gene was not pathogenic and corresponds to the predicted transcript variant of STK 11, which is derived from the genomic sequence of Chr19 (NT_011295).

Can tandem alternative splicing and evasion of premature termination codon surveillance contribute to attenuated Peutz–Jeghers syndrome?

It is suggested that nucleotide changes creating or disrupting tandem alternative splice sites are a pertinent disease mechanism and require contextualization for clinical reporting and that some pathogenic STK11 variants cause an attenuated phenotype.

Splicing Error in E1α Pyruvate Dehydrogenase mRNA Caused by Novel Intronic Mutation Responsible for Lactic Acidosis and Mental Retardation*

An intronic point mutation was identified in the E1α PDH gene from a boy with delayed development and lactic acidosis, an X-linked disorder associated with a partial defect in pyruvate dehydrogenase (PDH) activity, and is responsible for the aberrant splicing phenotype.

Further observations on LKB1/STK11 status and cancer risk in Peutz–Jeghers syndrome

To obtain precise estimates of risk associated with PJS requires further studies of genotype–phenotype especially with respect to LKB1/STK11 negative cases, as this group is likely to be heterogeneous.

PMS2 gene mutational analysis: direct cDNA sequencing to circumvent pseudogene interference.

This approach is based on the selective amplification of PMS2 transcripts in two overlapping 1.6-kb RT-PCR products and allows to effectively identify deletions, splice mutations, and de novo retrotransposon insertions that escape the detection of most DNA-based mutation analysis protocols.

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