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ABSTRACT: LIM homeodomain transcription factors regulate many aspects of development in multicellular organisms. LHX4/Lhx4 is a protein that is essential for pituitary development and motor neuron specification in mammals. In human, a heterozygous splicing mutation of the LHX4 gene was reported in a family with combined pituitary hormone deficiencies (CPHD). In addition to CPHD, these patients were characterized by small sella turcica and chiari malformation. Here we report a Japanese patient with CPHD (GH, PRL, TSH, LH, FSH, and ACTH deficiency) due to a novel missense mutation (P366T) of the LHX 4 gene. She showed severe respiratory disease and hypoglycemia soon after birth. Brain MRI demonstrated hypoplastic anterior pituitary, ectopic posterior lobe, a poorly developed sella turcica, and chiari malformation. Sequence analysis of the LHX 4 gene identified a heterozygous missense mutation (P366T) in exon 6, which was present in LIM4 specific domain. Neither of the patient's parents harbored this mutation, indicating de novo mutation.
Endocrine Journal 09/2007; 54(4):637-41. · 2.03 Impact Factor
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ABSTRACT: Bartter syndrome (BS) type 1, also referred to antenatal BS, is a genetic tubulopathy with hypokalemic metabolic alkalosis and prenatal onset of polyuria leading to polyhydramnios. It has been shown that BS type 1 is caused by mutations in the SLC12A1 gene encoding bumetanide-sensitive Na-K-2Cl (-) cotransporter (NKCC2). We had the opportunity to care for two unrelated Japanese patients of BS type 1 with typical manifestations including polyhydramnios, prematurity, hypokalemia, alkalosis, and infantile-onset nephrocalcinosis. Analysis of the SLC12A1 gene demonstrated four novel mutations: N117X, G257S, D792fs and N984fs. N117X mutation is expected to abolish most of the NKCC2 protein, whereas G257, which is evolutionary conserved, resides in the third transmembrane domain. The latter two frameshift mutations reside in the intra-cytoplasmic C-terminal domain, which illustrates the importance of this domain for the NKCC2 function. In conclusion, we found four novel SLC12A1 mutations in two BS type 1 patients. Development of effective therapy for hypercalciuria is mandatory to prevent nephrocalcinosis and resultant renal failure.
Endocrine Journal 02/2007; 54(6):1003-7. · 2.03 Impact Factor
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ABSTRACT: Cough variant asthma has recently been described, mainly as airway inflammation in relation to bronchial asthma, but the relationship between the two types of asthma remains unclear. Further studies of cough receptor sensitivity are necessary to fully characterize cough variant asthma.
We assessed the relevance of testing cough sensitivity using an Astograph with continuous capsaicin inhalation, and compared the results with those obtained using intermittent inhalation. We showed the clinical applicability of testing cough sensitivity (0.156-80 microM capsaicin; five or more coughs, 1 minute of continuous inhalation at each concentration) using this method. We compared cough sensitivity among patients with pure cough variant asthma who did not develop bronchial asthma after an observation period of at least 1 year, patients with bronchial asthma and healthy individuals.
The continuous cough sensitivity test using the Astograph was reproducible and reliable. Cough sensitivity in patients with pure cough variant asthma was significantly higher than that in healthy individuals.
The cough sensitivity of patients with cough variant asthma is not necessarily identical to that of healthy individuals.
Allergology International 07/2006; 55(2):149-55.
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ABSTRACT: HESX1/Hesx1 is a member of the paired-like class of homeobox genes and is essential for pituitary and forebrain development. Mice with a targeted homozygous deletion of the Hesx1 show severe central nervous system defects, absence of optic vesicles, and a very small anterior pituitary gland. This phenotype is similar to the abnormalities observed in the human disorder called septo-optic dysplasia, a syndromic form of congenital hypopituitarism. To date, four missense mutations in the human HESX1 have been described in individuals with phenotypes ranging from severe septo-optic dysplasia, relatively mild combined pituitary hormone deficiency (CPHD), to isolated GH deficiency. Here we report a Japanese patient with CPHD (GH, TSH, LH, FSH, and ACTH deficiency) due to a novel sporadic HESX1 mutation. Brain magnetic resonance imaging examination revealed hypoplastic anterior pituitary, ectopic posterior lobe, and left optic nerve hypoplasia. Molecular analysis identified the insertion of a heterozygous mutation (306/307ins AG) in the exon 2 of the HESX1. This mutation changes a reading frame and introduces a premature stop codon soon after the mutation site. Therefore, this mutation would be predicted to generate a protein lacking the carboxyl-terminal homebox domain (DNA-binding domain) and cause the disease. Family analysis demonstrated that neither of the patient's parents harbored this mutation, indicating that the mutation had arisen de novo. In conclusion, a de novo heterozygous frameshift mutation in exon 2 of the HESX1 causes severe CPHD with optic nerve hypoplasia in a human.
Journal of Clinical Endocrinology & Metabolism 02/2003; 88(1):45-50. · 6.50 Impact Factor
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ABSTRACT: Some patients develop asthmatic symptoms such as wheezing and dyspnea during the course of cough variant asthma (CVA), which are considered precursors of classical asthma.
To identify the characteristics of such patients, we investigated the nature of CVA patients with or without developing bronchial asthma in the longitudinal study.
In 28 CVA patients whom we could observe over 5 years, duration of coughing, physical examination findings, pulmonary function and bronchial hyperresponsiveness to inhaled methacholine were retrospectively assessed.
Of these patients with CVA, 10 developed the asthmatic symptoms of wheezing and dyspnea (precursors of classical asthma) over 5 years. All these 10 patients showed marked bronchial hyperresponsiveness; however, there were no significant differences in the bronchial responsiveness to methacholine between patients with precursors of classical asthma and pure CVA patients who did not wheeze. The duration of coughing had a significant relationship with precursors of classical asthma. Seven patients with precursors of classical asthma developed wheezing in the first year and 1 patient each in the second, third and fourth year.
These findings of a 5-year observation suggest that longer duration of coughing may be an important factor that develops precursors of classical asthma in patients with CVA.
Respiration 72(6):606-11. · 2.26 Impact Factor
