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Bax?2 Family Alternative Splicing Salvages Bax Microsatellite-Frameshift Mutations.

ABSTRACT: Mutation or aberrant splicing can interrupt gene expression. Tumor suppressor Bax is one of the susceptible genes prone to microsatellite frameshifting mutations in coding regions. As a result, tumors exhibiting microsatellite instability (MSI) often present a "Bax-negative" phenotype. We previously reported that some Bax-negative cells in fact contain a functional Bax isoform (Bax?2), generated when unique alternative splicing "salvages" the shifted reading frame introduced by a microsatellite mutation. Here we compared Bax alternative splicing profiles in a range of cell lines and primary tumors with and without Bax microsatellite mutations. We found that MSI tumors exhibit a high Bax alternative splicing frequency, especially in exon 2, and produce a family of alternatively spliced isoforms that retain many important Bax functional domains. Surprisingly, these Bax?2 family isoforms can rescue Bax from all common microsatellite frameshift mutations. Production of Bax?2 requires specific cis mutations, while trans components are not cell-type specific. Furthermore, all Bax?2 family isoforms are more potent cell death inducers than the parental Bax without directly targeting mitochondria. These results indicate that the Bax?2 family can potentially salvage Bax tumor suppressor expression otherwise lost to mutation.

SUBMITTER: Haferkamp B

PROVIDER: S-EPMC3877669 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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BaxΔ2 Family Alternative Splicing Salvages Bax Microsatellite-Frameshift Mutations.

Haferkamp Bonnie B Zhang Honghong H Kissinger Samuel S Wang Xin X Lin Yuting Y Schultz Megan M Xiang Jialing J

Genes & cancer 20131101 11-12

Mutation or aberrant splicing can interrupt gene expression. Tumor suppressor Bax is one of the susceptible genes prone to microsatellite frameshifting mutations in coding regions. As a result, tumors exhibiting microsatellite instability (MSI) often present a "Bax-negative" phenotype. We previously reported that some Bax-negative cells in fact contain a functional Bax isoform (BaxΔ2), generated when unique alternative splicing "salvages" the shifted reading frame introduced by a microsatellite ...[more]

PMID: 24386510

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Project description:BackgroundCongenital adrenal hyperplasia (CAH) is a heterogeneous group of adrenal steroidogenesis disorders with variable degrees of glucocorticoid, mineralocorticoid and sex steroid deficiencies. CYP11A1 gene encodes the mitochondrial cholesterol side-chain cleavage enzyme (P450scc), which initiates the first reaction in steroidogenesis by converting cholesterol to pregnenolone. Variants in this gene are extremely rare but associated with severe forms of CAH due to its early and critical function in various steroid biosynthesis pathways. Here, we report a CYP11A1 exonic homozygous variant that, although exonic in location, affects splicing by creating an additional aberrant splicing site with frameshift and truncation of the gene.Patients and methodsThe proband is a 23-year old 46,XY patient raised as a girl. She was a product of normal pregnancy for first-degree relative parents. Soon after birth, she had vomiting, dehydration, hypotension, hyponatremia and hyperkalemia. She was started on glucocorticoids and mineralocorticoids with prompt recovery. Apart from a chronic need for these medications, her neonatal and childhood history was unremarkable. She sought medical advice at age 19 years for delayed puberty with primary amenorrhea and lack of breast development. On evaluation, she had normal external female genitalia, no breast development, undescended testes and absent uterus and ovaries. Her hormonal evaluation revealed very low estrogen, testosterone, cortisol, aldosterone, 17-hydroxyprogesterone, and androstenedione levels. ACTH, LH, FSH and renin were very high consistent with primary gonadal and adrenal failure. Her parents are healthy first-degree cousins. She has three sisters, all with 46,XX karyotype. One of them is clinically and biochemically normal while the other two sisters have normal female phenotype, normal uterus and ovaries, similar hormonal profile to the proband but different karyotype (46,XX) and absence of undescended testes. gDNA was used for whole exome sequencing (WES). Sanger sequencing was performed to confirm the detected variant and its segregation with the disease.ResultsWES identified a homozygous missense variant in CYP11A1 changing the second nucleotide (GCG > GTG) at position 189 in exon 3 and resulting in a change of Alanine to Valine (p.Ala189Val). This variant was confirmed by PCR and Sanger sequencing. It was found in a homozygous form in the proband and her two affected sisters and in a heterozygous form in the unaffected sister. In-silico analysis predicted this variant to create a new splicing site with frameshift and truncation of the gene transcript. This was confirmed by isolation of RNA, cDNA synthesis, gel electrophoresis and sequencing.ConclusionWe describe a family with a very rare form of CAH due to a CYP11A1 variant leading to creation of a new splice site, frameshift and premature truncation of the protein.

Dataset Information

Bax?2 Family Alternative Splicing Salvages Bax Microsatellite-Frameshift Mutations.

Publications

BaxΔ2 Family Alternative Splicing Salvages Bax Microsatellite-Frameshift Mutations.

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