NICOLA JUAN PABLO
Congresos y reuniones científicas
Título:
A NOVEL MUTATION IN THE SODIUM/IODIDE SYMPORTER CARBOXY-TERMINUS UNCOVERS A CRITICAL TRYPTOPHAN-ACID DOMAIN REQUIRED FOR PLASMA MEMBRANE TARGETING
Autor/es:
MARTIN, M; PEYRET, V; SIGNORINO, M; TESTA, G; MODENUTTI, C; SOBRERO, G; MUÑOZ, L; MARTI, M; MASINI-REPISO, AM; NICOLA, JP
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 dyshormonogenesis congenital hypothyroidism
that results from inactivating mutations in the slc5a5 gene ? which encodes the sodium iodide symporter (NIS). The clinical
and biochemical presentation of ITD include low to absent thyroid and salivary iodide accumulation and, if untreated, the
patients develop a variable degree of hypothyroidism, goiter, and even mental retardation. Objectives: To determine if a pediatric
patient with a clinical phenotype of ITD harbors an inactivating mutation in the slc5a5 gene, and if so, to ascertain the
molecular mechanisms of the effect of the mutation on the biogenesis and activity of NIS. Methods: The whole coding region
of the slc5a5 was PCR-amplified and subjected to Sanger sequencing, and in silico computational and in vitro functional studies
of a newly identified NIS mutation were performed. Results and conclusions: We report a novel homozygous missense
and loss-of-function mutation in the slc5a5 gene as a cause of ITD in a pediatric patient with dyshormonogenic congenital
hypothyroidism. The patient carries a G>A transition at position +1.682 in exon 14 resulting in a Gly to Glu substitution at
residue 561 (G561E) not previously reported in public reference exome databases. We show that G561E markedly reduces
iodide uptake when the protein is heterologously expressed in MDCK-II cells, because targeting of G561E NIS to the plasma
membrane is severely impaired. Replacing G561 with Gln also resulted in severe intracellular retention, suggesting that a bulky
side-chain rather than a negative charge at position 561 interferes with NIS cell surface trafficking. Bioinformatics and biochemical
analysis indicates that G561E impair the recognition of an adjacent tryptophan-acid domain by the kinesin light chain 2,
thus impairing mutant NIS exit from the endoplasmic reticulum and subsequent plasma membrane targeting. Altogether, our
results indicate that a small residue at position 561 is required for NIS maturation and plasma membrane trafficking. Of note,
comparison of slc5a5 gene sequence across different species indicates a high conservation of the kinesin light chain 2-recognized
tryptophan-acid domain.
follicular cell to actively accumulate iodide. ITD is an uncommon cause of dyshormonogenesis congenital hypothyroidism
that results from inactivating mutations in the slc5a5 gene ? which encodes the sodium iodide symporter (NIS). The clinical
and biochemical presentation of ITD include low to absent thyroid and salivary iodide accumulation and, if untreated, the
patients develop a variable degree of hypothyroidism, goiter, and even mental retardation. Objectives: To determine if a pediatric
patient with a clinical phenotype of ITD harbors an inactivating mutation in the slc5a5 gene, and if so, to ascertain the
molecular mechanisms of the effect of the mutation on the biogenesis and activity of NIS. Methods: The whole coding region
of the slc5a5 was PCR-amplified and subjected to Sanger sequencing, and in silico computational and in vitro functional studies
of a newly identified NIS mutation were performed. Results and conclusions: We report a novel homozygous missense
and loss-of-function mutation in the slc5a5 gene as a cause of ITD in a pediatric patient with dyshormonogenic congenital
hypothyroidism. The patient carries a G>A transition at position +1.682 in exon 14 resulting in a Gly to Glu substitution at
residue 561 (G561E) not previously reported in public reference exome databases. We show that G561E markedly reduces
iodide uptake when the protein is heterologously expressed in MDCK-II cells, because targeting of G561E NIS to the plasma
membrane is severely impaired. Replacing G561 with Gln also resulted in severe intracellular retention, suggesting that a bulky
side-chain rather than a negative charge at position 561 interferes with NIS cell surface trafficking. Bioinformatics and biochemical
analysis indicates that G561E impair the recognition of an adjacent tryptophan-acid domain by the kinesin light chain 2,
thus impairing mutant NIS exit from the endoplasmic reticulum and subsequent plasma membrane targeting. Altogether, our
results indicate that a small residue at position 561 is required for NIS maturation and plasma membrane trafficking. Of note,
comparison of slc5a5 gene sequence across different species indicates a high conservation of the kinesin light chain 2-recognized
tryptophan-acid domain.
