A case of congenital familial goiter with impaired thyroglobulin (Tg) synthesis has been reported. The patient is the fifth in a family of six children, three of whom have a goiter. The parents are cousins. The patient's thyroid function tests showed low T4 (1.0 μg/dl) and free T4 (0.2ng/dl), normal or slightly increased T3 (1.8ng/ml) and free T3 (7.4pg/ml), and high TSH (57μ/ml). Serum Tg was 5.1ng/ml (normal<30). The thyroidal 123I-uptake was 59.8% before and 54.5% after perchlorate test. Gel filtration with Bio-Gel A 5m demonstrated the presence of albumin-like protein probably iodinated as a major protein in the thyroid and very low content of Tg which was smaller than the normal 19S Tg. Histologically microfollicular adenoma and negative Tg immunostaining were the dominant findings. Segregation of Tg alleles in the family was studied by Southern blotting with a probe revealing a diallelic RFLP. The results demonstrated that the affected siblings had received the same alleles from both parents and were homozygous for the RFLP. Northern blotting analysis of the goiter RNA with a Tg probe revealed that, whereas the amount of Tg mRNA was normal, its size seemed slightly reduced. PCR amplification of Tg mRNA as six overlapping cDNA fragments demonstrated that a 200bp fragment was missing from the 5′ region of the goiter mRNA. Subcloning and sequencing of the cDNA fragments, and of the patient's genomic DNA amplified from this region, revealed that this aberrant splicing is due to a cytosine to guanine transversion at position minus 3 in the acceptor splice site of intron 3. The presence in exon 4 of a putative donor tyrosine residue (tyr 130) involved in thyroid hormone formation provides a coherent explanation of the hypothyroid status of the patient. To our knowledge, this is the first identified mutation responsible for congenital familial goiter in humans.
