A novel mutation in the TPO gene in goitrous hypothyroid patients with iodide organification defect.
OBJECTIVE
To screen and subsequently sequence the TPO gene for mutations in patients with congenital goitre, hypothyroidism and evidence for an organification defect (positive perchlorate discharge test).


METHODS
We have studied seven hypothyroid and congenitally goitrous patients from three unrelated families.


METHODS
We have measured serum thyroid hormone levels, 131I uptake, serum TSH and serum Tg concentrations. Denaturing gradient gel electrophoresis (DGGE) of PCR amplified genomic DNA was used to screen for mutations in the TPO gene.


RESULTS
DGGE identified the presence of two frameshift mutations: a GGCC duplication in exon 8 (homozygous in one family and heterozygous in the other family) and a heterozygous insertion of a single nucleotide (C) at position 2505-2511 in exon 14. In addition, we have detected an alteration in exon 11, not yet described in the literature, derived from a single nucleotide substitution of a C to G at position 2008, altering the well-conserved amino acid domain among the peroxidases superfamily. This mutation in exon 11 was present in two families that showed heterozygous mutation for exon 8 or for exon 14.


CONCLUSIONS
These results could support the hypothesis for a putative compound heterozygosity pattern in the affected patients. The altered phenotype (goitre and hypothyroidism since birth) seems justifiable in view of the possible inactivating character of this novel mutation in exon 11.
Santos
C L
CL
Thyroid Unit, Division of Endocrinology, University of Sao Paulo Medical School, Sao Paulo, Brazil.
Bikker
H
H
Rego
K G
KG
Nascimento
A C
AC
Tambascia
M
M
De Vijlder
J J
JJ
Medeiros-Neto
G
G
D000293:Adolescent; D000328:Adult; D002648:Child; D003409:Congenital Hypothyroidism; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D016368:Frameshift Mutation; D006042:Goiter / Q000151:congenital* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics / Q000378:metabolism; D007453:Iodide Peroxidase / Q000235:genetics*; D008297:Male; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
D007453:Iodide Peroxidase