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Andreas Hoeflich, Yi Yang, Wolfgang Rascher, Werner F Blum, Stefan Huber, Gabriele Koepf, Helmut J Kolb and Wieland Kiess

Hoeflich A, Yang Y, Rascher W, Blum WF, Huber S, Koepf G, Kolb HJ, Kiess W. Coordinate expression of insulin-like growth factor II (IGF-II) and IGF-II/mannose-6-phosphate receptor mRNA and stable expression of IGF-I receptor mRNA during differentiation of human colon carcinoma cells (Caco-2). Eur J Endocrinol 1996;135:49–59. ISSN 0804–4643

Insulin-like growth factor II (IGF-II) has been implicated in the differentiation of skeletal muscle cells. In this study the putative role of IGF-II in epithelial cell differentiation was investigated. The expression of IGF-II, IGF-1 receptor and IGF-II/mannose-6-phosphate receptor (IGF-II/M6P receptor) mRNA during spontaneous differentiation of the colon carcinoma cell line Caco-2 was measured. In addition, differentiation of Caco-2 cells during the cell culture period (days 1–21 in culture) was studied in parallel using morphological (light and scanning electron microscopy) and biochemical markers of growth (DNA, RNA and protein content, and β-actin mRNA and glyceraldehyde phosphate dehydrogenase mRNA expression) and differentiation (alkaline phosphatase activity, carcinoembryonic antigen content). A putative correlation between the markers of growth and differentiation and IGF gene expression was studied using linear regression analysis. Expression of IGF-II mRNA and IGF-II/M6P receptor mRNA correlated significantly with the progress of differentiation, while the IGF-I receptor was stably expressed throughout the culture period and exhibited a crucial role for the survival of Caco-2 cells, as shown by blocking experiments employing the monoclonal anti-IGF-I receptor antibody alpha-IR3. We hypothesize that: IGF-II mRNA and IGF-II/M6P receptor mRNA are expressed in a coordinate fashion during the differentiation of Caco-2 cells; coordinate expression of IGF-II and of IGF-II/M6P receptor mRNA might point to a role for IGF-II as a growth stimulant and for the IGF-II/M6P receptor for a regulator of IGF-II bioavailability in differentiating cells; alternatively, high IGF-II/M6P receptor mRNA and protein expression in differentiated cells but low IGF-II binding to the IGF-II/M6P receptor point to an important intracellular role of this receptor type in differentiated colon epithelial cells; the IGF-I receptor mRNA is stably expressed during the differentiation process of Caco-2 cells; the IGF-I receptor protein seems to be a prerequisite for the survival of Caco-2 cells.

W Kiess, Children's Hospital, Justus Liebig University, Feulgenstr. 12, D-35385 Giessen, Germany

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Jing Jin, Lingfeng Cao, Zhuhui Zhao, Shuixian Shen, Wieland Kiess, Dijing Zhi, Rong Ye, Ruoqian Cheng, Lian Chen, Yi Yang and Feihong Luo

Context

Congenital generalized lipodystrophy (CGL) is a rare and heterogeneous disease of autosomal recessive inheritance. Until now, no genetic findings had been reported in Chinese patients with CGL.

Objective

To analyze Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) and 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) gene variation in a Chinese boy with CGL and his family.

Design, setting, and participants

All exons of BSCL2 and AGPAT2 with adjacent intron–exon junctions were analyzed using direct sequencing.

Main outcome measures

Sequences of each exon and nearby intron of the BSCL2 and AGPAT2 genes of the family members were compared with the gene bank genomic sequences.

Results

DNA sequence analysis of the entire coding regions and surrounding uncoding regions disclosed a novel homozygous G→T mutation at nucleotide 909 in exon 5 of the BSCL2 gene in the affected child. A heterozygous state of the G→T mutation of the BSCL2 gene was also found in other family members. This mutation predicts the substitution of glutamic acid at codon 189 by the stop codon (Glu189X or E189X). No variation was found in the AGPAT2 gene.

Conclusion

E189X is a novel BSCL2 gene mutation that contributes to CGL formation in a family of Chinese origin.

Free access

Jeng-Chuan Shiang, Chih-Jen Cheng, Ming-Kai Tsai, Yi-Jen Hung, Yu-Juei Hsu, Sung-Sen Yang, Shi-Jye Chu and Shih-Hua Lin

Objective

To characterize the course of therapy in a large cohort of Chinese patients with thyrotoxic periodic paralysis (TPP), a reversible electrolyte emergency fraught with therapeutic challenges.

Design and methods

In this prospective interventional study, 78 patients with TPP (75 males and three females with an age range of 16–48 years) were consecutively enrolled over a 6-year period. Intravenous KCl at a rate of 10 mmol/h was administered until muscle strength recovered. Serum potassium (K+) and phosphorus concentrations were measured hourly during the paralytic attack and for 6 h after recovery.

Results

The serum potassium (K+) on attack was 2.1±0.2 mmol/l. The dose of KCl administered to restore muscle strength was 63±32 mmol, and peak serum K+ concentration after recovery was 5.3±0.5 mmol/l. A paradoxical fall in serum K+ concentration >0.1 mmol/l difference between presentation and treatment nadir was observed in approximately one-fourth of TPP patients (n=20). These patients had significantly higher serum-free thyroxine concentration, systolic blood pressure, and heart rate on presentation, as well as serum phosphate concentration on recovery. They not only needed much more KCl supplementation (104±34 vs 48±19 mmol, P<0.001), but also had significantly more severe rebound hyperkalemia (5.8±0.5 vs 5.1±0.4 mmol/l, P<0.001) on recovery than those who did not have paradoxical hypokalemia. There was a positive correlation between the dose of KCl administered and the difference between peak and nadir serum K+ (Δ K+) (r=0.68, P<0.001).

Conclusions

TPP patients who do not develop paradoxical hypokalemia need a smaller KCl dose to achieve recovery, whereas those who develop paradoxical hypokalemia have more severe hyperthyroidism and hyperadrenergic activity and may require blockage of intracellular K+ shift to prevent rebound hyperkalemia.

Free access

Shyang-Rong Shih, Mao-Shin Lin, Hung-Yuan Li, Hsin-Yi Yang, Yung-Lien Hsiao, Met-Ting Chang, Chung-Ming Chen and Tien-Chun Chang

Objective

Pretibial myxedema (PM) is a manifestation of Graves' disease (GD). Currently, its diagnosis depends on physicians' observation and biopsy. No satisfactory, objective, and non-invasive tool is available to record and investigate lesions. Digital infrared thermal imaging (DITI) detects surface temperature, and sonography reflects composition changes in soft tissue. This study was aimed to observe changes in DITI and sonography in PM, and to evaluate their clinical usefulness.

Methods

Nineteen GD patients with PM, 22 GD patients with mild diffuse non-pitting edema over lower legs, 46 GD patients with normal appearance of lower legs, and 14 normal volunteers were recruited for observation with DITI; 8, 21, 21, and 11 of them respectively also received soft tissue sonography for investigating the pathogenesis of DITI change.

Results

Lower leg temperatures of normal volunteers decreased gradually from proximal to distal parts. In all 19 patients with PM, DITI showed abnormally low focal temperatures over the lesions. In GD patients with mild diffuse non-pitting edema and GD patients with normal appearance of lower legs, DITI showed abnormally low focal temperature in 90.9 and 65.2% of the patients respectively. Areas of clinically visible PM and low focal temperature detected by DITI were sonographically characterized with increased skin thickness, hypoechoic substance deposition in the cutaneous tissue, and blurred boundary lines between dermis and subcutaneous tissue. TSH receptor antibody level correlated positively and significantly with skin thickness change and adjusted temperature difference between the center of temperature defect and the surrounding skin (P=0.046 and 0.033 respectively).

Conclusions

By using DITI and sonography, we detected characteristic changes in PM. These techniques are helpful in recording and may be useful tools to detect early changes of PM.

Open access

Feng Sun, Jun-Xiu Zhang, Chang-Yi Yang, Guan-Qi Gao, Wen-Bin Zhu, Bing Han, Le-Le Zhang, Yue-Yue Wan, Xiao-Ping Ye, Yu-Ru Ma, Man-Man Zhang, Liu Yang, Qian-Yue Zhang, Wei Liu, Cui-Cui Guo, Gang Chen, Shuang-Xia Zhao, Ke-Yi Song and Huai-Dong Song

Objective

Congenital hypothyroidism (CH), the most common neonatal metabolic disorder, is characterized by impaired neurodevelopment. Although several candidate genes have been associated with CH, comprehensive screening of causative genes has been limited.

Design and methods

One hundred ten patients with primary CH were recruited in this study. All exons and exon–intron boundaries of 21 candidate genes for CH were analyzed by next-generation sequencing. And the inheritance pattern of causative genes was analyzed by the study of family pedigrees.

Results

Our results showed that 57 patients (51.82%) carried biallelic mutations (containing compound heterozygous mutations and homozygous mutations) in six genes (DUOX2, DUOXA2, DUOXA1, TG, TPO and TSHR) involved in thyroid hormone synthesis. Autosomal recessive inheritance of CH caused by mutations in DUOX2, DUOXA2, TG and TPO was confirmed by analysis of 22 family pedigrees. Notably, eight mutations in four genes (FOXE1, NKX2-1, PAX8 and HHEX) that lead to thyroid dysgenesis were identified in eight probands. These mutations were heterozygous in all cases and hypothyroidism was not observed in parents of these probands.

Conclusions

Most cases of congenital hypothyroidism in China were caused by thyroid dyshormonogenesis rather than thyroid dysgenesis. This study identified previously reported causative genes for 57/110 Chinese patients and revealed DUOX2 was the most frequently mutated gene in these patients. Our study expanded the mutation spectrum of CH in Chinese patients, which was significantly different from Western countries.

Free access

Feng Cai, Yi-Dan Zhang, Xiuli Zhao, Ya-Kun Yang, Si-Hai Ma, Cong-Xin Dai, Xiao-Hai Liu, Yong Yao, Ming Feng, Jun-Ji Wei, Bing Xing, Yong-Hui Jiao, Zhen-Qing Wei, Zhen-Ming Yin, Bo Zhang, Feng Gu and Ren-Zhi Wang

Objective

The aryl hydrocarbon receptor interacting protein gene (AIP) is associated with pituitary adenoma (PA). AIP has not been sequenced in East Asian PA populations, so we performed this study in a Han Chinese cohort.

Design

Our study included six familial PA pedigrees comprising 16 patients and 27 unaffected relatives, as well as 216 sporadic PA (SPA) patients and 100 unrelated healthy controls.

Methods

AIP sequencing was carried out on genomic DNA isolated from blood samples. Multiplex ligation-dependent probe amplification and microsatellite marker analyses on DNA from the paired tumor tissues were performed for loss of heterozygosity analysis.

Results

We identified three common and four rare single nucleotide polymorphisms (SNPs), one intron insertion, one novel synonymous variant, four novel missense variants, and a reported nonsense mutation in three familial isolated PA (FIPA) cases from the same family. Large genetic deletions were not observed in the germline but were seen in the sporadic tumor DNA from three missense variant carriers. The prevalence of AIP pathogenic variants in PA patients here was low (3.88%), but was higher in somatotropinoma patients (9.30%), especially in young adults (≤30 years) and pediatric (≥18 years) paients (17.24% and 25.00% respectively). All AIP variant patients suffered from macroadenomas. However, the AIP mutation rate in FIPA families was low in this cohort (16.67%, 1/6 families).

Conclusion

AIP gene mutation may not be frequent in FIPA or SPA from the Han Chinese population. AIP sequencing and long-term follow-up investigations should be performed for young patients with large PAs and their families with PA predisposition.