The insulin receptor () gene was analyzed in four patients with severe insulin resistance, revealing five novel mutations and a deletion that removed exon 2. A patient with Donohue syndrome (DS) had a novel p.V657F mutation in the second fibronectin type III domain (FnIII-2), which contains the α-β cleavage site and part of the insulin-binding site. The mutant INSR was expressed in Chinese hamster ovary cells, revealing that it reduced insulin proreceptor processing and impaired activation of downstream signaling cascades. Using online databases, we analyzed 82 missense mutations and demonstrated that mutations causing DS were more frequently located in the FnIII domains than those causing the milder type A insulin resistance ( = 0.016). In silico structural analysis revealed that missense mutations predicted to severely impair hydrophobic core formation and stability of the FnIII domains all caused DS, whereas those predicted to produce localized destabilization and to not affect folding of the FnIII domains all caused the less severe Rabson-Mendenhall syndrome. These results suggest the importance of the FnIII domains, provide insight into the molecular mechanism of severe insulin resistance, will aid early diagnosis, and will provide potential novel targets for treating extreme insulin resistance.
Abstract.We performed genetic analysis and clinical investigations for three patients with
suspected monocarboxylate transporter 8 (MCT8) deficiency. On genetic analysis of the
MCT8(SLC16A2) gene, novel mutations (c.1333C>A;
p.R445S, c.587G>A; p.G196E and c.1063_1064insCTACC; p.R355PfsX64) were identified in
each of three patients. Although thyroid function tests (TFTs) showed the typical pattern
of MCT8 deficiency at the time of genetic diagnosis in all patients, two patients
occasionally were euthyroid. A TRH test revealed low response, exaggerated response and
normal response of TSH, respectively. Endocrinological studies showed gonadotropin (Gn)
deficiency in two adult patients. On ultrasonography, goiter was detected in one patient.
Interestingly, pituitary magnetic resonance imaging (MRI) demonstrated atrophy and
thinness of the pituitary gland in two patients. Our findings suggest that thyroid status
in patients with MCT8 deficiency varies with time of examination, and repeated TFTs are
necessary for patients suspected of MCT8 deficiency before genetic analysis. In addition,
it is noteworthy that some variations were observed on the TRH test and ultrasonography of
the thyroid gland in the present study. Morphological abnormality of the pituitary gland
may be found in some patients, while Gn deficiency should be considered as one of the
complications.
A nine-month-old boy, with functional disomy for Xq26-qter and multiple congenital abnormalities, is reported. The boy had severe pre- and postnatal growth retardation, profound developmental delay, hypotonia, microcephaly, agenesis of the corpus callosum, dysmorphic facial features, cryptorchidism, and left multidysplastic kidney. He developed feeding difficulties and infantile spasms. G-banding analysis of his chromosomes showed additional material on the short arm of chromosome 21. His parents refused to submit to chromosome analysis. Analysis with chromosome microdissection followed by reverse and forward chromosome painting indicated his karyotype as 46,XY,der(21)t(X;21)(q26;p11.2). This is the first description of pure functional disomy for Xq26-qter due to an unbalanced X-autosome translocation.
Abstract. We experienced a case of fetal goitrous hypothyroidism in an infant delivered by a 33-year-old woman receiving 300 mg/day of propylthiouracil (PTU) for hyperthyroidism due to Graves' disease. A large fetal goiter (maximum diameter, 60 mm) was detected by magnetic resonance imaging (MRI) at 36 weeks of gestation. Initial fetal blood sampling revealed hypothyroidism with a serum thyroid-stimulating hormone (TSH) of 99 µIU/mL, free triiodothyronine (T 3 ) of 1.97 pg/mL, and free thyroxine (T 4 ) of 0.29 ng/dL. Consequently, a diagnosis of fetal goitrous hypothyroidism due to transplacental passage of maternal PTU was made. To reduce the risk of perinatal complications, 300 µg of levothyroxine sodium (L-T 4 ) was administered into the maternal amniotic fluid twice between 37 and 38 weeks of gestation. Subsequent fetal MRI showed that the size of goiter had decreased. At 38 weeks and 5 days of gestation, a 3042-g male infant was born by cesarean section. There were no severe complications at delivery, although mild tachypnea was observed and the infant's thyroid gland was slightly enlarged. He was treated with L-T 4 for two weeks. At present, his growth and neurological development are normal. This case indicates that intrauterine therapy by the intraamniotic administration of L-T 4 can be effective in treating fetal goitrous hypothyroidism even during late gestation.
Abstract. We carried out screening for mutations in the GH-1 gene in 29 sporadic Japanese subjects with severe Isolated Growth Hormone Deficiency (IGHD) by dideoxy fingerprinting (ddF). Three of 29 (N 10%) were heterozygous for each of the following GH-1 gene mutations including: 1) an G--'A transition in the third codon of the GH-1 signal peptide of exon 1 resulting in a Threonine to Alanine substitution, 2) a G--~A transition in the first base of the donor splice site of IVS 3 (+1G--A) and 3) a G-' A transition in the 183rd codon of the GH-1 mature peptide of exon 5 resulting in an Arginine to Histidine substitution.One of three was heterozygous for both mutations of 1) and 2). The IVS 3 (+1G-~A) mutation has been previously reported in affected individuals from three unrelated families with IGHD type II (autosomal dominant form). This mutation destroys the GH IVS 3 donor splice site, causing skipping of exon 3 and loss of the codons for amino acids 32-71 of the mature GH peptide. Our findings indicate that 1) ddF screening of genomic DNAs provides a practical tool to detect GH gene mutations and 2) some sporadic cases of IGHD may be caused by GH gene alternations.
It is known that hypothyroidism delays puberty in mammals. Interaction between the hypothalamo-pituitary-thyroid (HPT) and hypothalamo-pituitary-gonadal (HPG) axes may be important processes in delayed puberty. Gonadotropin-inhibitory hormone (GnIH) is a newly discovered hypothalamic neuropeptide that inhibits gonadotropin synthesis and release in quail. It now appears that GnIH is conserved across various mammals and primates, including humans, and inhibits reproduction. We have further demonstrated that GnIH is involved in pubertal delay induced by thyroid dysfunction in female mice. Hypothyroidism delays pubertal onset with the increase in hypothalamic GnIH expression and the decrease in circulating gonadotropin and estradiol levels. Thyroid status regulates GnIH expression by epigenetic modification of the GnIH promoter region. Furthermore, knockout of GnIH gene abolishes the effect of hypothyroidism on delayed pubertal onset. Accordingly, it is considered that GnIH is a mediator of pubertal disorder induced by thyroid dysfunction. This is a novel function of GnIH that interacts between the HPT-HPG axes in pubertal onset delay. This mini-review summarizes the structure, expression, and function of GnIH and highlights the action of GnIH in pubertal disorder induced by thyroid dysfunction.
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