Two novel and correlated CF-causing insertions in the (TG)mTn tract of the CFTR gene

Silvia Pierandrei; Giovanna Blaconà; Benedetta Fabrizzi; Giuseppe Cimino; Natalia Cirilli; Nicole Caporelli; Antonio Angeloni; Marco Cipolli; Marco Lucarelli

doi:10.1371/journal.pone.0222838

Two novel and correlated CF-causing insertions in the (TG)mTn tract of the CFTR gene

PLoS One. 2019 Oct 8;14(10):e0222838. doi: 10.1371/journal.pone.0222838. eCollection 2019.

Authors

Silvia Pierandrei¹, Giovanna Blaconà², Benedetta Fabrizzi³, Giuseppe Cimino⁴, Natalia Cirilli³, Nicole Caporelli³, Antonio Angeloni², Marco Cipolli³, Marco Lucarelli^{2

5}

Affiliations

¹ Dept. of Mother-Child and Urologic Sciences, Sapienza University of Rome, Rome, Italy.
² Dept. of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
³ Cystic Fibrosis Care Center, Mother - Child Department, United Hospitals, Ancona, Italy.
⁴ Cystic Fibrosis Care Center, Umberto I Hospital, Rome, Italy.
⁵ Pasteur Institute Cenci Bolognetti Foundation, Rome, Italy.

Abstract

Two novel and related pathogenic variants of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene were structurally and functionally characterized. These alterations have not been previously described in literature. Two patients with diagnosis of Cystic Fibrosis (CF) based on the presence of one mutated allele, p.Phe508del, pathological sweat test and clinical symptoms were studied. To complete the genotypes of both patients, an extensive genetic and functional analysis of the CFTR gene was performed. Extensive genetic characterization confirmed the presence of p.Phe508del pathogenic variant and revealed, in both patients, the presence of an insertion of part of intron 10 in intron 9 of the CFTR gene, within the (TG)m repeat, with a variable poly-T stretch. The molecular lesions resulted to be very similar in both patients, with only a difference in the number of T in the poly-T stretch. The functional characterization at RNA level revealed a complete anomalous splicing, without exon 10, from the allele with the insertion of both patients. Consequently, the alleles with the insertions are expected not to contribute to the formation of a functional CFTR protein. Molecular and functional features of these alterations are compatible with the definition of novel CF-causing variants of the CFTR gene. This also allowed the completion of the genetic characterization of both patients.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Alleles
Base Sequence / genetics*
Child
Cystic Fibrosis / genetics*
Cystic Fibrosis / pathology
Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
Exons / genetics
Female
Genotype
Humans
Introns / genetics
Male
Mutagenesis, Insertional / genetics
Mutation / genetics
RNA Splicing / genetics

Substances

CFTR protein, human
Cystic Fibrosis Transmembrane Conductance Regulator

Grants and funding

This work was supported by Regione Lazio (research projects 2008 – 2012). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.