NICOLA JUAN PABLO
Congresos y reuniones científicas
Título:
NOVEL HOMOZYGOUS NA+/I- SYMPORTER (NIS) GENE VARIANTS OF UNKNOWN CLINICAL SIGNIFICANCE ASSOCIATED WITH DYSHORMONOGENETIC CONGENITAL HYPOTHYROIDISM
Autor/es:
NICOLA, JP; SIGNORINO, M; TESTA, G; SOBRERO, G; MUÑOZ, L; MIRAS, M; MASINI-REPISO, AM
Lugar:
Rio de Janeiro
Reunión:
Congreso; XVI Congreso de la Sociedad Latinoamericana de Tiroides; 2017
Institución organizadora:
Sociedad Latinoamericana de Tiroides
Resumen:
Introduction: Iodide transport defect (ITD) is an autosomal recessive disorder whose hallmark is the inability of the thyroid
follicular cell to actively accumulate iodide. ITD is an uncommon cause of dyshormonogenetic congenital hypothyroidism that
results from inactivating mutations in the sodium iodide symporter (NIS)-coding gene. Clinical manifestations include low to
absent iodide accumulation in the thyroid tissue and, if untreated, the patients develop a variable degree of hypothyroidism,
goiter, and even mental retardation. Objectives: The objective of this work was to investigate the presence of inactivating
mutations in the gene encoding NIS in two unrelated pediatric patients with a clinical phenotype of ITD. Methods: The
genomic DNA encoding all fifteen NIS-coding gene exons were PCR-amplified and further subjected to Sanger sequencing.
Moreover, bioinformatics analysis of the newly identified NIS variants was performed using the software Alamut. Results and
conclusions: We identify two homozygous variants in the DNA sequence encoding NIS in two unrelated pediatric patients
with dyshormonogenetic congenital hypothyroidism. The patients were homozygous for the variants c.1673A>C in exon 11
and c.1973C>T in exon 13, respectively. Significantly, both variants were silent but not observed in the genome of 50 healthy
controls, and therefore classified as variants of unknown clinical significance. Bioinformatics analysis revealed that both variants
are potentially deleterious for normal NIS mRNA splicing to maintain the open reading frame. The variant c.1673A>C would
result in the disruption of a splicing enhancer located in exon 11 and retention of intron 11, originating the putative mutant
p.P443fsX86 NIS. Whereas c.1973C>T would result in a novel splicing silencer in exon 13 and retention of intron 13, originating
the putative mutant T550fsX3 NIS. Future experiments using functional in vivo mini-gene splicing assays are required
to fully characterize the impact of the variants on splicing defects. In conclusion, we identified two novel NIS variants of unknown
clinical significance associated with dyshormonogenetic congenital hypothyroidism. These variants may lead to potential
mis-splicing defects causing structural changes in NIS molecules that impair its normal biogenesis and activity, thus leading to
congenital hypothyroidism.
follicular cell to actively accumulate iodide. ITD is an uncommon cause of dyshormonogenetic congenital hypothyroidism that
results from inactivating mutations in the sodium iodide symporter (NIS)-coding gene. Clinical manifestations include low to
absent iodide accumulation in the thyroid tissue and, if untreated, the patients develop a variable degree of hypothyroidism,
goiter, and even mental retardation. Objectives: The objective of this work was to investigate the presence of inactivating
mutations in the gene encoding NIS in two unrelated pediatric patients with a clinical phenotype of ITD. Methods: The
genomic DNA encoding all fifteen NIS-coding gene exons were PCR-amplified and further subjected to Sanger sequencing.
Moreover, bioinformatics analysis of the newly identified NIS variants was performed using the software Alamut. Results and
conclusions: We identify two homozygous variants in the DNA sequence encoding NIS in two unrelated pediatric patients
with dyshormonogenetic congenital hypothyroidism. The patients were homozygous for the variants c.1673A>C in exon 11
and c.1973C>T in exon 13, respectively. Significantly, both variants were silent but not observed in the genome of 50 healthy
controls, and therefore classified as variants of unknown clinical significance. Bioinformatics analysis revealed that both variants
are potentially deleterious for normal NIS mRNA splicing to maintain the open reading frame. The variant c.1673A>C would
result in the disruption of a splicing enhancer located in exon 11 and retention of intron 11, originating the putative mutant
p.P443fsX86 NIS. Whereas c.1973C>T would result in a novel splicing silencer in exon 13 and retention of intron 13, originating
the putative mutant T550fsX3 NIS. Future experiments using functional in vivo mini-gene splicing assays are required
to fully characterize the impact of the variants on splicing defects. In conclusion, we identified two novel NIS variants of unknown
clinical significance associated with dyshormonogenetic congenital hypothyroidism. These variants may lead to potential
mis-splicing defects causing structural changes in NIS molecules that impair its normal biogenesis and activity, thus leading to
congenital hypothyroidism.
