Biomedical subjects

G D Frechtel

Publications and source records attributed to G D Frechtel.

3 recordsLinked to original sources

PubMed1998

Evidence for the segregation of three different mutated alleles of the thyroglobulin gene in a Brazilian family with congenital goiter and hypothyroidism.

We have previously reported a Brazilian family with congenital goiter, hypothyroidism, and marked impairment of thyroglobulin (Tg) synthesis. Analysis of the Tg mRNA in the goiter of one of the siblings revealed a cytosine to thymine transition creating a stop codon at position 1510. This point mutation is removed from the majority of Tg mRNA transcripts by the preferential generation in the goiter of a 171 nt deleted Tg mRNA by alternative splicing. The nonsense mutation destroys a TaqI site at this position in the mutant Tg gene. Using polymerase chain reaction (PCR) amplification and TaqI digestion we found that two siblings affected with goiter and hypothyroidism, as well as the father and three siblings with normal thyroid function, are all heterozygous for the nonsense mutation. This implies that an additional mutation must be present in the affected individuals, generating a compound heterozygote genotype. A new polymorphism within the thyroglobulin gene represented by three alleles has been detected. This was documented by the TaqI restriction enzyme and phTgM3 probe hybridization that showed a three allelic polymorphism with fragment sizes of 16.5 kb (allele A), 14.5 kb (allele B) and 11.0 kb (allele C). Segregation analysis of these alleles in the family indicated that the two affected siblings were homozygous for the allele C. In contrast the unaffected father and three other siblings, who carried the nonsense mutation, were heterozygous for alleles B and C. Analysis of the Tg genotypes implies that two additional mutations of the Tg gene must segregate in this family to account for the observed phenotypes.

Adult↗

PubMed1994

Molecular genetics of hereditary thyroid diseases due to a defect in the thyroglobulin or thyroperoxidase synthesis.

1. Hereditary goiter and the various degrees of thyroid hypofunction are the result of structural changes in the thyroglobulin (Tg) or thyroperoxidase (TPO) proteins, the inability to couple iodotyrosines or defective iodination, impairing or substantially altering the synthesis of T4 and T3. 2. The first mutations in the Tg and TPO genes responsible for human cases of dyshormonogenesis have been described. The mutation in two siblings with hereditary goiter and marked impairment of Tg synthesis was a cytosine to thymine transition creating a stop codon at position 1510. The point mutation is removed by the preferential accumulation of a 171-nt deleted Tg mRNA. In another subject, molecular studies revealed that exon 4 was missing from the major Tg transcript due to a cytosine to guanine transversion at position minus 3 in the acceptor splice site of intron 3. 3. Genomic DNA studies identified a duplication of a 4-base sequence in the eighth exon of the TPO gene. Interestingly, besides abolishing the enzymatic activity by disrupting the reading frame of the messenger RNA and introducing stop codons, the GGCC duplication also unmasks a cryptic acceptor splice site in exon 9. 4. In conclusion, the identification of different molecular defects provided evidence that hereditary goiter associated with abnormal Tg or TPO synthesis is caused by heterogeneous genetic alterations.

Amino Acid Sequence↗

PubMed1993

Human thyroid tissue do not express thyroalbumin.

Thyroid tissue total RNAs from multinodular goiter (G2) and from hereditary goiter with defective Tg synthesis (JNA) were hybridized with a 5'albumin cDNA probe (F-47), a 3' albumin cDNA probe (B-44) and a thyroglobulin cDNA probe (phTgM3). JNA refers to tissue obtained from a patient with virtual absence of Tg in thyroid tissue and the presence of increased concentration of an albumin-like labeled protein in the thyroid. No hybridization signal was detected in both G2 and JNA with albumin probes at Northern Blot studies. Those results were confirmed by dot-blot analysis of total RNA where no hybridization signal was detected in G2 and JNA. To confirm that thyroid tissues do not express thyroalbumin total RNA from JNA and normal control thyroid tissue (C) were amplified by PCR using albumin and Tg primers. An expected fragment of 592 bp was observed in a human liver sample with the albumin primers. However JNA and C samples showed absence of an amplification product of the same size. We concluded that thyroid cells do not contain the albumin transcript. Albumin is probably taken up from circulation and iodinated by the thyroid follicular cell with subsequent release of iodoalbumin into the circulation.

Albumins↗