Chronic Hyponatremia Causes Neurologic and Psychologic Impairments.

Hyponatremia is the most common clinical electrolyte disorder. Once thought to be asymptomatic in response to adaptation by the brain, recent evidence suggests that chronic hyponatremia may be linked to attention deficits, gait disturbances, risk of falls, and cognitive impairments. Such neurologic defects are associated with a reduction in quality of life and may be a significant cause of mortality. However, because underlying diseases such as adrenal insufficiency, heart failure, liver cirrhosis, and cancer may also affect brain function, the contribution of hyponatremia alone to neurologic manifestations and the underlying mechanisms remain unclear. Using a syndrome of inappropriate secretion of antidiuretic hormone rat model, we show here that sustained reduction of serum sodium ion concentration induced gait disturbances; facilitated the extinction of a contextual fear memory; caused cognitive impairment in a novel object recognition test; and impaired long-term potentiation at hippocampal CA3-CA1 synapses. In vivo microdialysis revealed an elevated extracellular glutamate concentration in the hippocampus of chronically hyponatremic rats. A sustained low extracellular sodium ion concentration also decreased glutamate uptake by primary astrocyte cultures, suggesting an underlying mechanism of impaired long-term potentiation. Furthermore, gait and memory performances of corrected hyponatremic rats were equivalent to those of control rats. Thus, these results suggest chronic hyponatremia in humans may cause gait disturbance and cognitive impairment, but these abnormalities are reversible and careful correction of this condition may improve quality of life and reduce mortality.

A role for myosin Va in cerebellar plasticity and motor learning: a possible mechanism underlying neurological disorder in myosin Va disease.

Mutations of the myosin Va gene cause the neurological diseases Griscelli syndrome type 1 and Elejalde syndrome in humans and dilute phenotypes in rodents. To understand the pathophysiological mechanisms underlying the neurological disorders in myosin Va diseases, we conducted an integrated analysis at the molecular, cellular, electrophysiological, and behavioral levels using the dilute-neurological (d-n) mouse mutant. These mice manifest an ataxic gait and clonic seizures during postnatal development, but the neurological disorders are ameliorated in adulthood. We found that smooth endoplasmic reticulum (SER) rarely extended into the dendritic spines of Purkinje cells (PCs) of young d-n mice, and there were few, if any, IP(3) receptors. Moreover, long-term depression (LTD) at parallel fiber-PC synapses was abolished, consistent with our previous observations in juvenile lethal dilute mutants. Young d-n mice exhibited severe impairment of cerebellum-dependent motor learning. In contrast, adult d-n mice showed restoration of motor learning and LTD, and these neurological changes were associated with accumulation of SER and IP(3) receptors in some PC spines and the expression of myosin Va proteins in the PCs. RNA interference-mediated repression of myosin Va caused a reduction in the number of IP(3) receptor-positive spines in cultured PCs. These findings indicate that myosin Va function is critical for subsequent processes in localization of SER and IP(3) receptors in PC spines, LTD, and motor learning. Interestingly, d-n mice had defects of motor coordination from young to adult ages, suggesting that the role of myosin Va in PC spines is not sufficient for motor coordination.

Isolated growth hormone deficiency in two siblings because of paternal mosaicism for a mutation in the GH1 gene.

CONTEXT: Mutations in the GH1 gene have been identified in patients with isolated growth hormone deficiency (IGHD). Mutations causing aberrant splicing of exon 3 of GH1 that have been identified in IGHD are inherited in an autosomal dominant manner, whereas other mutations in GH1 that have been identified in IGHD are inherited in an autosomal recessive manner. OBJECTIVE: Two siblings born from nonconsanguineous healthy parents exhibited IGHD. To elucidate the cause, GH1 in all family members was analysed. RESULTS: Two novel mutations in GH1, a point mutation in intron 3 and a 16-bp deletion in exon 3, were identified by sequence analyses. The intronic mutation was present in both siblings and was predicted to cause aberrant splicing. The deletion was present in one of the siblings as well as the mother with normal stature and was predicted to cause rapid degradation of mRNA through nonsense-mediated mRNA decay. The point mutation was not identified in the parents' peripheral blood DNA; however, it was detected in the DNA extracted from the father's sperms. As a trace of the mutant allele was detected in the peripheral blood of the father using PCR-RFLP, the mutation is likely to have occurred de novo at an early developmental stage before differentiation of somatic cells and germline cells. CONCLUSIONS: This is the first report of mosaicism for a mutation in GH1 in a family with IGHD. It is clear that the intronic mutation plays a dominant role in the pathogenesis of IGHD in this family, as one of the siblings who had only the point mutation was affected. On the other hand, the other sibling was a compound heterozygote for the point mutation and the 16-bp deletion and it may be arguable whether IGHD in this patient should be regarded as autosomal dominant or recessive.

[Syndromes of resistance to thyroid hormone and inappropriate secretion of TSH (SITSH)].

Resistance to thyroid hormone (RTH) is a syndrome in which the responsiveness of end organs to thyroid hormone (TH) is reduced. Given that the TH-responsive end-organs include pituitary thyrotrophs, almost all patients with RTH manifest unsuppressed thyrotropin (TSH) despite elevated free-T4 and free-T3 levels. This abnormal finding in the thyroid function test is termed "syndrome of inappropriate secretion of TSH" (SITSH) or "central hyperthyroidism". Patients with TSH-secreting pituitary tumors(TSHoma) also manifest SITSH. Thus, the differential diagnosis of RTH vs. TSHoma is sometimes difficult and challenging. In this review article, the etiology of RTH and diagnostic approach for SITSH are explained and an algorithm for differential diagnosis of RTH vs. TSHoma is proposed.

Long-term management of recurrent papillary thyroid carcinoma treated with lenvatinib for over 5 years: a case report.

BACKGROUND: Few reports exist of the long-term management of recurrent and progressive papillary thyroid carcinoma (PTC) with a tyrosine kinase inhibitor for over 5 years. CASE PRESENTATION: A 57-year-old woman was referred to a psychiatric hospital for the treatment of schizophrenia. The patient had been diagnosed with a PTC at the age of 40 and subsequently underwent a left thyroid lobectomy. At 47, completion total thyroidectomy and lymph node dissection were performed and the patient assessed as radioactive iodine refractory postoperatively. External radiation therapy was performed for Rouviere lymph nodes. At 57, neck and mediastinal lymph nodes, and lung metastases had progressed, and the trachea became narrowed by para-tracheal lymph node compression. After 2 weeks of sorafenib therapy on an outpatient basis, the patient was discovered unconsciousness at home and transferred to hospital by ambulance; sorafenib therapy was stopped. The patient was diagnosed with reversible posterior leukoencephalopathy syndrome by brain magnetic resonance imaging. External radiation therapy to the site of the tracheal stenosis in the neck and mediastinum was performed. The patient's mental symptoms worsened, and she was referred to a psychiatric hospital, Kachi Memorial Hospital, in July 2015. In September, the patient's mental state stabilized and in November, after computed tomography revealed rapid disease progression, lenvatinib was commenced at a daily dose of 24 mg. Measurable solid recurrence sites were neck lymph nodes in the pre-laryngeal subcutaneous space, right lobe of the lung, and left adrenal. After 3 months, the tumors shrank in a partial response (PR). Because of several adverse events, occasional dose reductions or discontinuations of lenvatinib were sometimes necessary. Since re-starting lenvatinib, treatment with this for 51 consecutive months was achieved while maintaining a PR. Although a new bone metastasis was noted after 57 months of lenvatinib, treatment was continued for another 9 months. The patient subsequently passed away in June 2021. CONCLUSIONS: The long-term treatment of recurrent PTC with lenvatinib was feasible, with manageable adverse events, for more than 5 years.

Time-dependent changes in proinflammatory and neurotrophic responses of microglia and astrocytes in a rat model of osmotic demyelination syndrome.

Osmotic demyelination syndrome (ODS) is a serious demyelinating disease in the central nervous system usually caused by rapid correction of hyponatremia. In an animal model of ODS, we previously reported microglial accumulation expressing proinflammatory cytokines. Microglia and astrocytes secreting proinflammatory cytokines and neurotrophic factors are reported to be involved in the pathogenesis of demyelinative diseases. Therefore, to clarify the role of microglial and astrocytic function in ODS, we examined the time-dependent changes in distribution, morphology, proliferation, and mRNA/protein expression of proinflammatory cytokines, neurotrophic factors, and matrix metalloproteinase (MMP) in microglia and astrocytes 2 days (early phase) and 5 days (late phase) after the rapid correction of hyponatremia in ODS rats. The number of microglia time dependently increased at demyelinative lesion sites, proliferated, and expressed tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, inducible nitric oxide synthase, and MMP2, 9, and 12 at the early phase. Microglia also expressed leukemia inhibitory factor (a neurotrophic factor) and phagocytosed myelin debris at the late phase. The number of astrocytes time dependently increased around demyelinative lesions, extended processes to lesions, proliferated, and expressed nerve growth factor and glial cell line-derived neurotrophic factor at the late phase. Moreover, treatment with infliximab, a monoclonal antibody against TNF-α, significantly attenuated neurological impairments. Our results suggest that the role of microglia in ODS is time dependently shifted from detrimental to protective and that astrocytes play a protective role at the late phase. Modulation of excessive proinflammatory responses in microglia during the early phase after rapid correction may represent a therapeutic target for ODS.

Frequent cyclic variation of heart rate is associated with left ventricular diastolic dysfunction in patients without ischemia.

BACKGROUND: Cyclic variation of heart rate (CVHR) associated with sleep-disordered breathing reflects cardiac autonomic responses to apneic/hypoxic stress. However, the association of CVHR with cardiac function is unclear. METHODS: We investigated a total of 181 patients who underwent both 24-hour Holter electrocardiography (ECG) and quantitative gated single-photon emission computed tomography (SPECT) myocardial functional imaging, excluding patients with atrial fibrillation, myocardial infarction, structural heart disease, and implantable devices, from January 2017 to July 2018. The number of CVHR per hour (CVHR index) in sleeping-time Holter ECG was compared with the parameters of left ventricular (LV) systolic and diastolic functions assessed by cardiac SPECT functional imaging, peak filling rate (PFR), first-third mean filling rate (1/3 MFR), and time to peak filling rate (TTPF). RESULTS: In all patients, the CVHR index was not associated with any parameters of cardiac functions. However, in a propensity score-matched subgroup of patients without ischemia (N = 39), the CVHR index was negatively correlated with PFR (r = -0.35, P < .05) and 1/3 MFR (r = -0.37, P < .05) but positively correlated with TTPF (r = 0.43, P < .01) and was not correlated with LV ejection fraction. Multivariate linear regression analysis revealed that high CVHR index was independently associated with LV diastolic dysfunction, even after adjusting for the relative wall thickness and LV mass index assessed by echocardiography. CONCLUSION: These results indicate that the high frequency of CVHR in sleeping time is associated with LV diastolic dysfunction in nonischemic patients, irrespective of LV geometry.

Folic acid prevents congenital malformations in the offspring of diabetic mice.

It is well known that maternal diabetes causes various congenital malformations. Although there are many reports that folic acid (FA) administration in pregnancy reduces the risk of birth defects including neural tube defects (NTDs), a precise analysis on the preventive effect of FA against diabetic embryopathy has not been done yet. In this study, we analyzed the preventive effects of FA on congenital malformations including NTDs, cardiovascular, and skeletal malformations using a diabetic mouse model. Female mice were rendered hyperglycemic by streptozotocin and then mated. Pregnant diabetic mice were treated daily with FA (3 mg/kg body weight) or saline between gestational days (GD) 6 and 10. On GD 18, fetuses were examined for congenital malformations. FA did not affect plasma glucose levels. In the DM control group, the incidence of NTDs, cardiovascular, and skeletal malformations was 28.4%, 28.5%, and 29.7%, respectively. In the FA-treated group, the corresponding proportions reduced to 6.0%, 2.5% and 12.5%, respectively. A whole-mount TUNEL revealed an increased apoptosis in the hindbrain region of embryos from DM control group on day 9.5, and the apoptosis was decreased by FA treatment. Maternal plasma homocysteine levels on GD 9.5 were significantly lowered in DM control group compared with those in non-DM group, and FA treatment did not show a significant effect. These results indicate that FA is effective for the prevention of various diabetic embryopathy including NTDs, cardiovascular, and skeletal malformations, and suggested that this effect is independent from homocysteine metabolism and possibly mediated by decreasing the abnormal apoptosis during organogenesis.

Possible involvement of BRAFV600E in altered gene expression in papillary thyroid cancer.

Somatic mutations in BRAF, especially BRAFV600E, are frequently identified in papillary thyroid cancer (PTC) tumors. It has been established that expression levels of numbers of genes are characteristically altered in PTC, however, the link between BRAF mutation and gene expression patterns are still elusive. In the present study, we analyzed relative expression levels of the wild type BRAF and BRAFV600E mRNA by using quantitative PCR (qPCR) and cDNAPCR- RFLP in 19 PTC specimens and adjacent normal thyroid tissues. BRAFV600E mRNA was detected in 17 out of 19 PTC specimens, and the expression levels were valuable among the specimens, suggesting alternative expression of BRAFV600E in each cell and/or alternative population of BRAFV600E-positive clones in the tumor. We then analyzed expression levels of 20 genes by qPCR, and analyzed for possible correlation with expression levels of BRAFV600E mRNA. Expression levels of fibronectin, vimentin and CITED1 (Cbp/p300 interacting protein with glutamic acid and aspartic acid rich carboxyl terminal domain) were positively correlated with those of BRAFV600E, suggesting pathophysiological links between activated BRAF and overexpression of these genes. Among these genes expression of vimentin was decreased by inhibiting BRAF expression in NPA cells that express BRAFV600E by means of siRNA, suggesting activated BRAF positively regulate expression of vimentin. Collectively, our analyses illustrated the possibilities that variable expression of BRAFV600E may modify characters of PTC through its effects on gene expression.

Requirement of DHCR24 for postnatal development of epidermis and hair follicles in mice.

Desmosterolosis is an autosomal recessive disorder with severe developmental anomalies due to mutations in the DHCR24 gene, encoding an enzyme to convert desmosterol to cholesterol. We reported that DHCR24 [knockout (KO)] mice were born with wrinkleless taut skin and with impaired development of epidermis. In this study, we investigated the postnatal development of epidermis and hair follicle in the skin of KO mice grafted to the nude mice. Skin graft was required since the KO mice die within few hours after birth. Forty days after the skin graft, epidermis from the KO mice revealed the characteristic phenotype observed at birth. Furthermore, the number of hair follicles in the skin graft from KO mice to the nude mice was significantly less and development was delayed than that from control. These findings implicate that DHCR24 plays important roles for normal development of epidermis and hair follicle even in postnatal life.

Insertion of an intracisternal A particle retrotransposon element in plasma membrane calcium ATPase 2 gene attenuates its expression and produces an ataxic phenotype in joggle mutant mice.

Using forward genetic analysis, we identified the insertion of an intracisternal A particle (IAP) retrotransposon element in the plasma membrane calcium ATPase 2 gene (Pmca2/Atp2b2) in the joggle mouse, a novel mutant that displays ataxic gait by postnatal day 12. Expression of Pmca2 mRNA in the joggle mouse is only 5% of that in the wild type mouse. The insertion is located 15 bp downstream of the donor splice site of the exon containing the initiation codon. Chimeric mRNA composed of the 5'-region of Pmca2 and the IAP element were detected, indicating that some of the primary transcripts are terminated by polyadenylation signals in long terminal repeats of the IAP element. We also identified cryptic splice sites in the IAP element that are likely involved in aberrant splicing of the Pmca2 primary transcripts that leads to rapid degradation of mRNA through nonsense mediated mRNA decay. Ataxia was observed in compound heterozygous mice carrying the joggle mutation and the wriggle mutation, a previously reported missense Pmca2 mutant. Thus, we attributed ataxia in joggle mice to reduced expression of Pmca2, resulting from insertion of the IAP element.

Long-term amiodarone treatment causes cardioselective hypothyroid-like alteration in gene expression profile.

The long-term cardiac effects of amiodarone resemble many aspects of hypothyroidism. The anti-arrhythmic potential of amiodarone may therefore be the result of a drug-induced, local hypothyroid-like condition. To investigate this controversial issue, we compared gene expression profiles in the hearts of rats treated with amiodarone with those of rats with hypothyroidism. Wistar male rats were assigned to 3 groups (n=6-8): Control, systemic hypothyroidism (hypothyroidism) and amiodarone treatment (amiodarone, 150 mg/kg/day, p.o., 4 weeks). Electrocardiogram (ECG) recordings, gene profiling by DNA microarray and Northern blotting were carried out. Amiodarone, like hypothyroidism, caused significant prolongation of RR and QT intervals in ECGs. Microarray analysis of 8435 genes in the left ventricular myocardium revealed a significant similarity in expression profiles between hypothyroidism and amiodarone (R=0.63, p<0.00001). The gene expression profiles of hypothyroidism and amiodarone showed closer correlation when top 100 up-regulated and 100 down-regulated genes in hypothyroidism (total 200 genes) were analyzed (R=0.78, p<0.00001). Northern blots of left ventricular myocardium showed a parallel decrease in mRNAs for myosin heavy chain (MHC)-alpha and a parallel increase for myosin heavy chain (MHC)-beta in hypothyroidism and amiodarone. In the liver and pituitary, in contrast, Northern blots showed quite different changes in the transcripts of the representative T3-responsive genes in the hypothyroidism and amiodarone. In conclusion, long-term treatment with amiodarone causes cardioselective hypothyroid-like alterations in gene expression profiles. The potent anti-arrhythmic activity of amiodarone may be attributable, in part at least, to this unique transcriptional remodeling.

Identification of genes differentially expressed in mouse fetuses from streptozotocin-induced diabetic pregnancy by cDNA subtraction.

Epidemiological studies have shown that the risks of fetal malformation such as neural tube defects increase in diabetic pregnancy. To explore the mechanism of fetal malformation induced by diabetes, cDNA subtraction using mouse embryos (E9.5) of diabetic dams and those of controls was performed to identify differentially expressed genes. The expression level of genes identified by cDNA subtraction was further verified by quantitative RT-PCR using E8.5 embryos, and differential expression of 4 genes, Brcc3, Commd3, Ddx1, and SET was confirmed. We also analyzed the expression level of neural tube defect-related genes, and found that Folbp1, EphrinA5 and Sox10 were differentially expressed. Altered expression of these genes mostly persisted throughout the later stages of the development (E10.5-14.5). Hierarchical clustering analysis showed correlation between expression levels of these genes, suggesting that these genes cooperatively play a role in embryonic development. Our results suggest that an altered gene expression profile in embryos underlies the development of congenital malformation in diabetic pregnancies.

Thyroglobulin gene mutations producing defective intracellular transport of thyroglobulin are associated with increased thyroidal type 2 iodothyronine deiodinase activity.

CONTEXT: Most patients with defective synthesis and/or secretion of thyroglobulin (Tg) present relatively high serum free T3 (FT3) concentrations with disproportionately low free T4 (FT4) resulting in a high FT3/FT4 ratio. The mechanism of this change in FT3/FT4 ratio remains unknown. OBJECTIVE: We hypothesize that increased type 2 iodothyronine deiodinase (D2) activity in the thyroid gland may explain the higher FT3/FT4 ratio that is frequently observed in patients with abnormal Tg synthesis. DESIGN: We recently identified a compound heterozygous patient (patient A) with a Tg G2356R mutation and one previously described (C1245R) that is known to cause a defect in intracellular transport of Tg. In the current study, after determining the abnormality caused by G2356R, we measured D2 activity as well as its mRNA level in the thyroid gland. We also measured the thyroidal D2 activity in three patients with Tg transport defect and in normal thyroid tissue. RESULTS: Morphological and biochemical analysis of the thyroid gland from patient A, complemented by a pulse-chase experiment, revealed that G2356R produces a defect in intracellular Tg transport. D2 activity but not type 1 deiodinase in thyroid glands of patients with abnormal Tg transport was significantly higher than in normal thyroid glands, whereas D2 mRNA level in patient A was comparable with that in normal thyroid glands. Furthermore, there was a positive correlation between D2 activity and FT3/FT4 ratios. CONCLUSION: Increased thyroidal D2 activity in the thyroid gland is responsible for the higher FT3/FT4 ratios in patients with defective intracellular Tg transport.

A case with isolated growth hormone deficiency caused by compound heterozygous mutations in GH-1: a novel missense mutation in the initiation codon and a 7.6kb deletion.

OBJECTIVE: To characterize the cause of a sporadic isolated growth hormone deficiency in a single patient. METHODS: Genomic DNA was extracted from blood samples of the patient and his family. Exons and exon-intron junctions of the GH-1 gene were amplified by PCR and sequenced. To characterize possible GH-1 deletions we performed Southern blot analysis and PCR-restriction fragment length analyses. RESULTS: An adenine to guanine mutation at the first nucleotide of the initiation codon (Met [ATG](-26)Val [GTG]) of the GH-1 gene was identified in the patient and the mother. A 7.6kb GH-1 deletion was identified in the patient, the brother and the father. CONCLUSION: The patient was a compound heterozygote for an allele bearing a Met(-26)Val missense mutation inherited from his mother and an allele containing deletion of the entire GH-1 gene inherited from his father. The present missense mutation has not been described previously. Attention should be paid to the heterozygous gene deletion that is difficult to detect by PCR-based genetic analysis. The patient responded to GH replacement therapy fairly well, without developing anti-hGH antibody.

Changes in Ucp1, D2 (Dio2) and Glut4 (Slc2a4) mRNA expression in response to short-term cold exposure in the house musk shrew (Suncus murinus).

The house musk shrew (Suncus murinus), or so-called suncus, is a cold-intolerant mammal, but it is unclear why it is susceptible to low temperatures. Cold-intolerance may be the result of lower thermogenic activity in brown adipose tissue (BAT). The early phase of severe cold exposure is a critical period for suncus. Therefore, we exposed suncus to mildly cold temperatures (10-12 degrees C) for 1 to 48 h to increase non-shivering thermogenesis without causing stress and measured changes in the expression of uncoupling protein 1 (Ucp1), type II iodothyronine 5'-deiodinase (Dio2=D2), and glucose transporter 4 (Slc2a4=Glut4) in BAT. These mRNAs play a major role in non-shivering thermogenesis and are mainly regulated by the sympathetic nervous system via direct beta-noradrenergic innervation of BAT. During cold exposure, Ucp1 expression in BAT increased steadily over time, albeit only slightly. Neither D2 nor Glut4 expression in BAT increased immediately; however, they had increased significantly after 24 h and 48 h of cold exposure. These findings suggest that the responsiveness of mRNA regulation is weak and thus may be involved in cold-intolerance in suncus.

Mapping of jog locus to the region between D6Mit104 and D6Mit336 on mouse chromosome 6.

The joggle mouse is a recessive ataxic mutant carrying an unknown mutation in a C3H/He (C3H)-derived chromosomal segment. Taking advantage of the mouse genome database, we selected 127 DNA microsatellite markers showing heterozygosity between C3H and C57BL/6J (B6) and a first round of screening for the joggle mutation was performed on B6-jog/+ partial congenic mice (N4). We identified 4 chromosomal regions in which 13 microsatellite markers show heterozygosity between C3H and B6. Then, we analyzed the genotype of these 4 chromosomal regions in mice that showed the joggle phenotype and mapped the jog locus between markers D6Mit104 (111.4 Mb) and D6Mit336 (125.1 Mb) (an interval of 13.7 Mb) on chromosome 6. By using a partial congenic strain together with the mouse genome database, we successfully mapped the chromosomal localization of the jog locus much more efficiently than by conventional linkage analysis.

DHCR24 gene knockout mice demonstrate lethal dermopathy with differentiation and maturation defects in the epidermis.

Desmosterolosis is an autosomal recessive disorder due to mutations in the 3beta-hydroxysterol-Delta24 reductase (DHCR24) gene that encodes an enzyme catalyzing the conversion of desmosterol to cholesterol. To date, only two patients have been reported with severe developmental defects including craniofacial abnormalities and limb malformations. We employed mice with targeted disruption of DHCR24 to understand the pathophysiology of desmosterolosis. All DHCR24-/- mice died within a few hours after birth. Their skin was wrinkleless and less pliant, leading to restricted movement and inability to suck (empty stomach). DHCR24 gene was expressed abundantly in the epidermis of control but not of DHCR24-/- mice. Accordingly, cholesterol was not detected whereas desmosterol was abundant in the epidermis of DHCR24-/- mice. Skin histology revealed thickened epidermis with few and smaller keratohyaline granules. Aberrant expression of keratins such as keratins 6 and 14 suggested hyperproliferative hyperkeratosis with undifferentiated keratinocytes throughout the epidermis. Altered expression of filaggrin, loricrin, and involcrin were also observed in the epidermis of DHCR24-/-. These findings suggested impaired skin barrier function. Indeed, increased trans-epidermal water loss and permeability of Lucifer yellow were observed in DHCR24-/- mice. DHCR24 thus plays crucial role for skin development and its proper function.

Haplotype analysis reveals founder effects of thyroglobulin gene mutations C1058R and C1977S in Japan.

CONTEXT: Thyroglobulin (Tg) mutations were previously believed to be rare, resulting in congenital goitrous hypothyroidism. However, an increasing number of patients with Tg mutations, who are euthyroid to mildly hypothyroid, have been identified in Japan. OBJECTIVES: The purpose of this study was to investigate whether the three frequently found Tg mutations, namely C1058R, C1245R, and C1977S, were caused by a founder effect. RESULTS: We found 26 different mutations within the Tg gene in 52 patients from 41 families. Thirty-five patients were homozygous for the mutations, whereas the others were compound heterozygous. The occurrence of Tg mutation within the general Japanese population is one in 67,000. Patients with the C1245R mutation were found throughout Japan, whereas those with the C1058R mutation were confined to a small village on a southern island, and those with the C1977S mutation were restricted to a city. The eight patients with the C1058R mutation and the seven patients with the C1977S mutation all showed the same combinations of 18 single-nucleotide polymorphisms in the coding region of the Tg gene, which would appear in one in 810 million and one in 37 billion, respectively, control subjects. CONCLUSIONS: The frequently found mutations, C1058R and C1977S, were caused by founder effects. This result suggests that Tg mutations may provide a genetic basis for the cause of familial euthyroid goiter.

Myosin Va mutation in rats is an animal model for the human hereditary neurological disease, Griscelli syndrome type 1.

A spontaneous neurological mutation, dilute-opisthotonus (dop), was discovered in our breeding colony of Wistar rats. We found that the mutation affected the gene encoding Myosin Va (MyoVA), an actin-based molecular motor. Analysis of the myosin Va (Myo5a) gene of the dop genome showed the presence of a complex rearrangement consisting of a 306-bp inversion associated with 217-bp and 17-bp deletions. A 141-bp exon is skipped in the dop transcript, producing a dop cDNA with a 141 in-frame deletion in the sequences encoding the head region. Expression of the MyoVA protein is severely impaired in the brains of dop homozygous rats, suggesting they have a null mutation for Myo5a. In a morphological analysis of the cerebella of dop rats, we found an absence of smooth endoplasmic reticulum (SER) and of inositol 1,4,5-triphosphate (IP3) receptors in the dendritic spines of Purkinje cells (PC). The SER acts as an intracellular Ca(2+) store and IP3-mediated Ca(2+) signaling in dendritic spines plays a critical role in synaptic regulation. We therefore measured synaptic transmission and long-term depression (LTD), a form of synaptic plasticity underlying cerebellar motor learning, at PC synapses in the cerebella of dop rats. We found that synaptic transmission at the PC synapses is largely normal, whereas the LTD is deficient due to a decrease in IP3-mediated Ca(2+) release from the SER in the PC spines of the dop cerebella. These findings may account for the ataxic movements and clonic convulsions displayed by dop rats. They also contribute to our understanding of the neurological disease mechanisms of the human hereditary disease Griscelli syndrome type 1, which is caused by mutation of the Myo5a gene.