Purpose: Heat shock transcription factor 4 (HSF4) regulates the expression of several heat shock ... more Purpose: Heat shock transcription factor 4 (HSF4) regulates the expression of several heat shock protein (HSP) genes. HSPs are one of the major components responsible for lens protein organization. Recently, we found that mutations of HSF4 result in hereditary cataract. In this study, we explore the role of HSF4 in the development of age-related cataract. Methods: We screened sequence variants of HSF4 in age-related cataract patients and the natural population from Shanghai, China. Results: In individuals of natural populations, we detected no single nucleotide polymorphism (SNP) with a frequency higher than 5% in a complete coding region or in their exon-intron boundaries. In 150 age-related cataract patients, we identified seven sequence changes. We found an intronic G→A transition (c.1020-25G>A) in one patient, a missense mutation (c.1078A>G) in exon 4 in two patients, a silent mutation (c.1223 C>T) in exon 5 in two patients, an intronic C→T transition (c.1256+25C>T) in one patient, and a silent mutation in exon 6 (c.1286 C>T) in one patient. These five variants were not represented in 220 control individuals. We also identified an intronic C→T transition (c.1019+9C>T) and a missense mutation (c.1243G>A) in exon 3 in three patients, but these two variants were also present in 100 control subjects. Conclusions: We identified five new HSF4 mutations in 150 age-related cataract patients, enlarging the spectrum of HSF4 mutations in cataract patients. This result indicates that HSF4 mutations account for only a small fraction of age-related cataracts.
Dentinogenesis imperfecta 1 (DGI1, MIM 125490) is an autosomal dominant dental disease characteri... more Dentinogenesis imperfecta 1 (DGI1, MIM 125490) is an autosomal dominant dental disease characterized by abnormal dentin production and mineralization. The DGI1 locus was recently refined to a 2-Mb interval on 4q21 (ref. 1). Here we study three Chinese families carrying DGI1. We find that the affected individuals of two families also presented with progressive sensorineural high-frequency hearing loss (gene DFNA39). We identified three disease-specific mutations within the dentin sialophosphoprotein gene (DSPP) in these three families. We detected a G-->A transition at the donor-splicing site of intron 3 in one family without DFNA39, a mutation predicted to result in the skipping of exon 3. In two other families affected with both DGI1 and DFNA39, however, we identified two independent nucleotide transversions in exons 2 and 3 of DSPP, respectively, that cause missense mutations of two adjacent amino-acid residues in the predicted transmembrane region of the protein. Moreover, transcripts of DSPP previously reported to be expressed specifically in teeth are also detected in the inner ear of mice. We have thus demonstrated for the first time that distinct mutations in DSPP are responsible for the clinical manifestations of DGI1 with or without DFNA39.
In this work, a highly integrated 14-band UWB transceiver is designed in a 0.13mum SiGe BiCMOS te... more In this work, a highly integrated 14-band UWB transceiver is designed in a 0.13mum SiGe BiCMOS technology. The chip consumes 425mW during receive mode and 380mW during transmit mode from a split power supply of 2.4 and 1.2V. In this architecture a divide and mix approach is selected to allow the use of a single PLL with one RF VCO and one loop filter. The transmitter is designed to reduce spurious emissions to -70dBm to support Japanese and European transmit mask requirements.
We established a recessive cataract model from a spontaneous mutation in the KUNMING outbred mice... more We established a recessive cataract model from a spontaneous mutation in the KUNMING outbred mice. Lens opacity appears 11 days after birth. Slit lamp examination reveals that the opacity mainly localizes to the nuclear region of the lens. Histological analysis shows a severe degeneration of the epithelial cells underneath the anterior lens capsule, whereas those cells in the equatorial region display an excessive proliferation and migration. Within the cortical area underneath the posterior lens capsule, both vacuoles and morgagnian-like bodies are seen. Blue-stained spherical bodies are observed in the embryonic nucleus, forming a Y-like pattern. We mapped the disease locus and found a homozygous G to A nucleotide conversion at position 489 of Crygs in mutant mice, leading to a truncated gene product (Trp163Stop). This finding suggests that CRYGS is not only a lens structural protein, but is also likely to be involved in epithelial cell proliferation, apoptosis, and migration.
Aims. Hereditary non-polyposis colorectal cancer, thyroid medullary carcinoma, breast/ovarian can... more Aims. Hereditary non-polyposis colorectal cancer, thyroid medullary carcinoma, breast/ovarian cancer and gastric cancer/breast cancer syndrome are encountered in surgery. Some gastric cancer/breast cancer syndrome may be the result of a CDH1 germline mutation. This is the first report of CDH1 germline mutations gastric cancer/breast cancer syndrome in Chinese patients.
Hereditary gingival fibromatosis (HGF, MIM 135300; approved gene symbol GINGF) is an oral disease... more Hereditary gingival fibromatosis (HGF, MIM 135300; approved gene symbol GINGF) is an oral disease characterized by enlargement of gingiva. Recently, a locus for autosomal dominant HGF has been mapped to an 11-cM region on chromosome 2p21. In the current investigation, we genotyped four Chinese HGF families using polymorphic microsatellite markers on 2p21. The HOMOG test provided evidence for genetic homogeneity, with evidence for linkage in four families (heterogeneity versus homogeneity test HOMOG, 2 ؍ 0.00). A cumulative maximum two-point lod score of 5.04 was produced with marker D2S390 at a recombination frequency of ؍ 0 in the four linked families. Haplotype analysis localized the hereditary gingival fibromatosis locus within the region defined by D2S352 and D2S2163. This region overlaps by 3.8 cM with the previously reported HGF region. Singlestrand conformation polymorphism and sequence analysis of the coding region of cytochrome P450 1B1 (CYP1B1) excluded it as a likely candidate gene.
Gingival fibromatosis (GINGF) is an oral disorder characterized by enlargement of the gingiva. It... more Gingival fibromatosis (GINGF) is an oral disorder characterized by enlargement of the gingiva. It occurs either as the sole phenotype or combined with other symptoms. Thus far, one GINGF locus has been mapped on chromosome 2, at 2p21, and a second possible locus has been mapped to 2p13. However, the genes responsible for this disorder have not been elucidated. We identified a four-generation Chinese GINGF family in which the disease manifests within 1 year after birth. After exclusion of the two known GINGF loci in this family, we performed a genomewide search to map the chromosome location of the responsible gene. We identified a new locus, GINGF2, on chromosome 5q13-q22 with a maximum two-point lod score of 4.31 at D5S1721 ( ؍ 0.00). Haplotype analysis placed the critical region in the interval defined by D5S1491 and D5S1453. Within this region, calcium/ calmodulin-dependent protein kinase IV (CAMK4) is a strong candidate.
Disseminated superficial porokeratosis (DSP) is a rare autosomal dominant epidermal keratinizatio... more Disseminated superficial porokeratosis (DSP) is a rare autosomal dominant epidermal keratinization disorder of lesions characterized by cornoid lamella with parakeratosis, hyperkeratosis, and loss of granular layers. The genetic basis for this disease is unknown. Through a proband with a diagnosis of DSP, we identified a large four-generation Chinese family with multiple DSP-affected members from Anhui province in China. After excluding the linkage of the disease phenotype to two known loci for disseminated superficial actinic porokeratosis in this family, we performed a genome-wide linkage analysis using 387 microsatellite markers and identified a novel disease locus for DSP at 18p11.3. Our subsequent fine mapping and haplotype analyses further narrowed down the disease locus into an 18.7 cM region between the telomere and D18S391 with a maximum two-point LOD (logarithm of the odds) score of 4.82 (theta =0.00) at D18S1138. Therefore, this study provides strong linkage evidence for a DSP locus at 18p11.3.
Ichthyosis vulgaris (IV) is an inherited scaling skin disorder with a prevalence estimated at 2.2... more Ichthyosis vulgaris (IV) is an inherited scaling skin disorder with a prevalence estimated at 2.29% in China. The gene responsible for this disorder has not been elucidated. To find the disease gene, we ascertained two Chinese IV families. Linkage analysis identified an IV locus on chromosome 1q22 with a maximum two-point Lod score of 2.47 at D1S1653 (θ=0.00). Haplotype analysis placed the critical region in a 7-cM interval defined by D1S1653 and D1S2675. These results provide the basis for further identifying the gene responsible for IV disorder.
Chromosome 5p, especially 5p15, involves in several cancers. To investigate its role in gastric c... more Chromosome 5p, especially 5p15, involves in several cancers. To investigate its role in gastric cancer, we analyzed 46 intestinal-type and 34 diffuse-type gastric cancers by Loss of heterozygosity (LOH). We found a high frequent LOH at 5p15.33, and identified a minimal 2.7 cM candidate region of tumor suppressor gene, encompassing four loci (D5S417, D5S2849, D5S1492 and D5S2088). In total 80 cases, the highest LOH occurs at D5S2849 (35.19%). In intestinal-type cases, the highest LOH frequency is 50%, whereas in diffuse-type cases, the highest is only 16.67%. By statistical analysis we also observed an obvious genotype-phenotype correlation on 5p15.3 (P!0.01).
Congenital cataracts cause 10-30% of all blindness in children, with one-third of cases estimated... more Congenital cataracts cause 10-30% of all blindness in children, with one-third of cases estimated to have a genetic cause. Lamellar cataract is the most common type of infantile cataract. We carried out whole-genome linkage analysis of Chinese individuals with lamellar cataract, and found that the disorder is associated with inheritance of a 5.11-cM locus on chromosome 16. This locus coincides with one previously described for Marner cataract. We screened individuals of three Chinese families for mutations in HSF4 (a gene at this locus that encodes heat-shock transcription factor 4) and discovered that in each family, a distinct missense mutation, predicted to affect the DNA-binding domain of the protein, segregates with the disorder. We also discovered an association between a missense mutation and Marner cataract in an extensive Danish family. We suggest that HSF4 is critical to lens development.
We describe here a spontaneous, autosomal recessive mutant mouse suffering from skin and hair def... more We describe here a spontaneous, autosomal recessive mutant mouse suffering from skin and hair defects, which arose in the outbred Kunming strain. By haplotype analysis and direct sequencing of PCR products, we show that this mutation is a new allele of the asebia locus with a naturally occurring mutation in the Scd1 gene (a CCC insertion at nucleotide position 835 in exon 5), which codes for stearoyl-CoA desaturase 1. This mutation introduces an extra proline residue at position 279 in the Scd1 protein. The mutant mice, originally designated km/km but now assigned the name Scd1 ab-Xyk (hereafter abbreviated as ab Xyk / ab Xyk ), have a similar gross and histological phenotype to that reported for previously characterized allelic asebia mutations ( Scd1 ab , Scd1 abJ , Scd1 ab2J , and Scd1 tm1Ntam ). Histological analysis showed they were also characterized by hypoplasic sebaceous glands and abnormal hair follicles. In a cross between Kunming- ab Xyk / ab Xyk and ABJ/Le- ab J / ab J mice, all the progeny showed the same phenotype, indicating that the two mutations were non-complementing and therefore allelic. Comparisons with the other four allelic mutants indicate that the Scd1 ab-Xyk mutation causes the mildest change in Scd1 function. This new mouse mutant is a good model not only for the study of scarring alopecias in humans, which are characterized by hypoplasic sebaceous glands, but also for studying the structure and function of the Scd1 protein.
Purpose: Heat shock transcription factor 4 (HSF4) regulates the expression of several heat shock ... more Purpose: Heat shock transcription factor 4 (HSF4) regulates the expression of several heat shock protein (HSP) genes. HSPs are one of the major components responsible for lens protein organization. Recently, we found that mutations of HSF4 result in hereditary cataract. In this study, we explore the role of HSF4 in the development of age-related cataract. Methods: We screened sequence variants of HSF4 in age-related cataract patients and the natural population from Shanghai, China. Results: In individuals of natural populations, we detected no single nucleotide polymorphism (SNP) with a frequency higher than 5% in a complete coding region or in their exon-intron boundaries. In 150 age-related cataract patients, we identified seven sequence changes. We found an intronic G→A transition (c.1020-25G>A) in one patient, a missense mutation (c.1078A>G) in exon 4 in two patients, a silent mutation (c.1223 C>T) in exon 5 in two patients, an intronic C→T transition (c.1256+25C>T) in one patient, and a silent mutation in exon 6 (c.1286 C>T) in one patient. These five variants were not represented in 220 control individuals. We also identified an intronic C→T transition (c.1019+9C>T) and a missense mutation (c.1243G>A) in exon 3 in three patients, but these two variants were also present in 100 control subjects. Conclusions: We identified five new HSF4 mutations in 150 age-related cataract patients, enlarging the spectrum of HSF4 mutations in cataract patients. This result indicates that HSF4 mutations account for only a small fraction of age-related cataracts.
Dentinogenesis imperfecta 1 (DGI1, MIM 125490) is an autosomal dominant dental disease characteri... more Dentinogenesis imperfecta 1 (DGI1, MIM 125490) is an autosomal dominant dental disease characterized by abnormal dentin production and mineralization. The DGI1 locus was recently refined to a 2-Mb interval on 4q21 (ref. 1). Here we study three Chinese families carrying DGI1. We find that the affected individuals of two families also presented with progressive sensorineural high-frequency hearing loss (gene DFNA39). We identified three disease-specific mutations within the dentin sialophosphoprotein gene (DSPP) in these three families. We detected a G-->A transition at the donor-splicing site of intron 3 in one family without DFNA39, a mutation predicted to result in the skipping of exon 3. In two other families affected with both DGI1 and DFNA39, however, we identified two independent nucleotide transversions in exons 2 and 3 of DSPP, respectively, that cause missense mutations of two adjacent amino-acid residues in the predicted transmembrane region of the protein. Moreover, transcripts of DSPP previously reported to be expressed specifically in teeth are also detected in the inner ear of mice. We have thus demonstrated for the first time that distinct mutations in DSPP are responsible for the clinical manifestations of DGI1 with or without DFNA39.
In this work, a highly integrated 14-band UWB transceiver is designed in a 0.13mum SiGe BiCMOS te... more In this work, a highly integrated 14-band UWB transceiver is designed in a 0.13mum SiGe BiCMOS technology. The chip consumes 425mW during receive mode and 380mW during transmit mode from a split power supply of 2.4 and 1.2V. In this architecture a divide and mix approach is selected to allow the use of a single PLL with one RF VCO and one loop filter. The transmitter is designed to reduce spurious emissions to -70dBm to support Japanese and European transmit mask requirements.
We established a recessive cataract model from a spontaneous mutation in the KUNMING outbred mice... more We established a recessive cataract model from a spontaneous mutation in the KUNMING outbred mice. Lens opacity appears 11 days after birth. Slit lamp examination reveals that the opacity mainly localizes to the nuclear region of the lens. Histological analysis shows a severe degeneration of the epithelial cells underneath the anterior lens capsule, whereas those cells in the equatorial region display an excessive proliferation and migration. Within the cortical area underneath the posterior lens capsule, both vacuoles and morgagnian-like bodies are seen. Blue-stained spherical bodies are observed in the embryonic nucleus, forming a Y-like pattern. We mapped the disease locus and found a homozygous G to A nucleotide conversion at position 489 of Crygs in mutant mice, leading to a truncated gene product (Trp163Stop). This finding suggests that CRYGS is not only a lens structural protein, but is also likely to be involved in epithelial cell proliferation, apoptosis, and migration.
Aims. Hereditary non-polyposis colorectal cancer, thyroid medullary carcinoma, breast/ovarian can... more Aims. Hereditary non-polyposis colorectal cancer, thyroid medullary carcinoma, breast/ovarian cancer and gastric cancer/breast cancer syndrome are encountered in surgery. Some gastric cancer/breast cancer syndrome may be the result of a CDH1 germline mutation. This is the first report of CDH1 germline mutations gastric cancer/breast cancer syndrome in Chinese patients.
Hereditary gingival fibromatosis (HGF, MIM 135300; approved gene symbol GINGF) is an oral disease... more Hereditary gingival fibromatosis (HGF, MIM 135300; approved gene symbol GINGF) is an oral disease characterized by enlargement of gingiva. Recently, a locus for autosomal dominant HGF has been mapped to an 11-cM region on chromosome 2p21. In the current investigation, we genotyped four Chinese HGF families using polymorphic microsatellite markers on 2p21. The HOMOG test provided evidence for genetic homogeneity, with evidence for linkage in four families (heterogeneity versus homogeneity test HOMOG, 2 ؍ 0.00). A cumulative maximum two-point lod score of 5.04 was produced with marker D2S390 at a recombination frequency of ؍ 0 in the four linked families. Haplotype analysis localized the hereditary gingival fibromatosis locus within the region defined by D2S352 and D2S2163. This region overlaps by 3.8 cM with the previously reported HGF region. Singlestrand conformation polymorphism and sequence analysis of the coding region of cytochrome P450 1B1 (CYP1B1) excluded it as a likely candidate gene.
Gingival fibromatosis (GINGF) is an oral disorder characterized by enlargement of the gingiva. It... more Gingival fibromatosis (GINGF) is an oral disorder characterized by enlargement of the gingiva. It occurs either as the sole phenotype or combined with other symptoms. Thus far, one GINGF locus has been mapped on chromosome 2, at 2p21, and a second possible locus has been mapped to 2p13. However, the genes responsible for this disorder have not been elucidated. We identified a four-generation Chinese GINGF family in which the disease manifests within 1 year after birth. After exclusion of the two known GINGF loci in this family, we performed a genomewide search to map the chromosome location of the responsible gene. We identified a new locus, GINGF2, on chromosome 5q13-q22 with a maximum two-point lod score of 4.31 at D5S1721 ( ؍ 0.00). Haplotype analysis placed the critical region in the interval defined by D5S1491 and D5S1453. Within this region, calcium/ calmodulin-dependent protein kinase IV (CAMK4) is a strong candidate.
Disseminated superficial porokeratosis (DSP) is a rare autosomal dominant epidermal keratinizatio... more Disseminated superficial porokeratosis (DSP) is a rare autosomal dominant epidermal keratinization disorder of lesions characterized by cornoid lamella with parakeratosis, hyperkeratosis, and loss of granular layers. The genetic basis for this disease is unknown. Through a proband with a diagnosis of DSP, we identified a large four-generation Chinese family with multiple DSP-affected members from Anhui province in China. After excluding the linkage of the disease phenotype to two known loci for disseminated superficial actinic porokeratosis in this family, we performed a genome-wide linkage analysis using 387 microsatellite markers and identified a novel disease locus for DSP at 18p11.3. Our subsequent fine mapping and haplotype analyses further narrowed down the disease locus into an 18.7 cM region between the telomere and D18S391 with a maximum two-point LOD (logarithm of the odds) score of 4.82 (theta =0.00) at D18S1138. Therefore, this study provides strong linkage evidence for a DSP locus at 18p11.3.
Ichthyosis vulgaris (IV) is an inherited scaling skin disorder with a prevalence estimated at 2.2... more Ichthyosis vulgaris (IV) is an inherited scaling skin disorder with a prevalence estimated at 2.29% in China. The gene responsible for this disorder has not been elucidated. To find the disease gene, we ascertained two Chinese IV families. Linkage analysis identified an IV locus on chromosome 1q22 with a maximum two-point Lod score of 2.47 at D1S1653 (θ=0.00). Haplotype analysis placed the critical region in a 7-cM interval defined by D1S1653 and D1S2675. These results provide the basis for further identifying the gene responsible for IV disorder.
Chromosome 5p, especially 5p15, involves in several cancers. To investigate its role in gastric c... more Chromosome 5p, especially 5p15, involves in several cancers. To investigate its role in gastric cancer, we analyzed 46 intestinal-type and 34 diffuse-type gastric cancers by Loss of heterozygosity (LOH). We found a high frequent LOH at 5p15.33, and identified a minimal 2.7 cM candidate region of tumor suppressor gene, encompassing four loci (D5S417, D5S2849, D5S1492 and D5S2088). In total 80 cases, the highest LOH occurs at D5S2849 (35.19%). In intestinal-type cases, the highest LOH frequency is 50%, whereas in diffuse-type cases, the highest is only 16.67%. By statistical analysis we also observed an obvious genotype-phenotype correlation on 5p15.3 (P!0.01).
Congenital cataracts cause 10-30% of all blindness in children, with one-third of cases estimated... more Congenital cataracts cause 10-30% of all blindness in children, with one-third of cases estimated to have a genetic cause. Lamellar cataract is the most common type of infantile cataract. We carried out whole-genome linkage analysis of Chinese individuals with lamellar cataract, and found that the disorder is associated with inheritance of a 5.11-cM locus on chromosome 16. This locus coincides with one previously described for Marner cataract. We screened individuals of three Chinese families for mutations in HSF4 (a gene at this locus that encodes heat-shock transcription factor 4) and discovered that in each family, a distinct missense mutation, predicted to affect the DNA-binding domain of the protein, segregates with the disorder. We also discovered an association between a missense mutation and Marner cataract in an extensive Danish family. We suggest that HSF4 is critical to lens development.
We describe here a spontaneous, autosomal recessive mutant mouse suffering from skin and hair def... more We describe here a spontaneous, autosomal recessive mutant mouse suffering from skin and hair defects, which arose in the outbred Kunming strain. By haplotype analysis and direct sequencing of PCR products, we show that this mutation is a new allele of the asebia locus with a naturally occurring mutation in the Scd1 gene (a CCC insertion at nucleotide position 835 in exon 5), which codes for stearoyl-CoA desaturase 1. This mutation introduces an extra proline residue at position 279 in the Scd1 protein. The mutant mice, originally designated km/km but now assigned the name Scd1 ab-Xyk (hereafter abbreviated as ab Xyk / ab Xyk ), have a similar gross and histological phenotype to that reported for previously characterized allelic asebia mutations ( Scd1 ab , Scd1 abJ , Scd1 ab2J , and Scd1 tm1Ntam ). Histological analysis showed they were also characterized by hypoplasic sebaceous glands and abnormal hair follicles. In a cross between Kunming- ab Xyk / ab Xyk and ABJ/Le- ab J / ab J mice, all the progeny showed the same phenotype, indicating that the two mutations were non-complementing and therefore allelic. Comparisons with the other four allelic mutants indicate that the Scd1 ab-Xyk mutation causes the mildest change in Scd1 function. This new mouse mutant is a good model not only for the study of scarring alopecias in humans, which are characterized by hypoplasic sebaceous glands, but also for studying the structure and function of the Scd1 protein.
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