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Growth arrest and DNA-damage-inducible protein 45 (Gadd45) family members have been implicated in DNA demethylation in vertebrates. However, it remained unclear how they contribute to the demethylation process. Here, we demonstrate that Gadd45a promotes active DNA demethylation through thymine DNA glycosylase (TDG) which has recently been shown to excise 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) generated in Ten-eleven-translocation (Tet)—initiated oxidative demethylation. The connection of Gadd45a with oxidative demethylation is evidenced by the enhanced activation of a methylated reporter gene in HEK293T cells expressing Gadd45a in combination with catalytically active TDG and Tet. Gadd45a interacts with TDG physically and increases the removal of 5fC and 5caC from genomic and transfected plasmid DNA by TDG. Knockout of both Gadd45a and Gadd45b from mouse ES cells leads to hypermethylation of specific genomic loci most of which are also targets of TDG and show 5fC enrichment in TDG-deficient cells. These observations indicate that the demethylation effect of Gadd45a is mediated by TDG activity. This finding thus unites Gadd45a with the recently defined Tet-initiated demethylation pathway.

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant disorder that affects craniofacial development and ovarian function. FOXL2 is the only gene known to be responsible for BPES. The majority of BPES patients show intragenic mutations of FOXL2. Recently, a 7.4 kb sequence disruption, which was 283 kb upstream of FOXL2, was identified to independently contribute to the BPES phenotype. Several breakpoints nearing FOXL2 (0 Mb to 1.2 Mb, several of which were distant from the 7.4 kb sequence disruption) have been mapped or deduced through a traditional method in BPES patients with chromosome reciprocal translocation. In this study, two BPES families with chromosome reciprocal translocation were investigated. Intragenic mutations of FOXL2 or pathogenic copy number variations were excluded for the two BPES families. All of the four breakpoints were identified at a base-precise manner using Giemsa banding and whole genome low-coverage sequencing (WGLCS). In family 01, the breakpoints were found at chr1:95,609,998 and chr3:138,879, 114 (213,132 bp upstream of FOXL2). In family 02, the breakpoints were located at chr3:138,665,431 (intragenic disruptions of FOXL2) and chr20:56,924,609. Results indicate that the intragenic and extragenic interruptions of FOXL2 can be accurately and rapidly detected using WGLCS. In addition, both the 213 kb upstream and intragenic interruptions of FOXL2 can cause BPES phenotype.

Shale gas is an important unconventional energy resource. However its only achieved successful commercial exploitation in the United States and Canada. Shale gas well QY1 was carried out in southeast Chongqing.Taking this well as a case, the fracturing design optimization workflow and its practice are described in this paper. The fracturing feasibility of well QY1 was firstly determined by referencing all the physical parameters of target formation. Then the reservoir stress model was revised and reservoir stress profile was established as well. The reservoir simulation software (Eclipse) was applied to build reservoir geological model for predicting the gas production and determine the optimized permeability enhanced area (PEA). The unconventional fracturing model (UFM) was used to optimize the fluid volume and fracturing scale. And the final fracturing plan was made based on the optimized conclusions. This optimization workflow and the good result provide reliable technique support for the development of the shale gas reservoir in this area. Key Words: Shale gas, PEA, Fracture propagation model, UFM, Production predicting model, Optimization

Objective To investigate the changes of regulatory T cells (Tregs) and whether Tregs can modulate the distribution of macrophage subtypes in visceral adipose tissue in the early stage of obesity.Methods After C57BL/6 mice obesity models were successfully established,metabolic parameters and numbers of Tregs and M1/M2 macrophage were measured at 4,10,and 20 weeks.The changes of metabolic parameters and adipose tissue inflammation in obesity mice after rapamycin intervention were evaluated. Results The early-stage obesity models were successfully established.Compared with normal diet mice,high fat diet mice had significantly higher epididymal adipose tissue mass and serum leptin levels(P0.05).However,there was no statistical difference in blood glucose and insulin levels between these two groups(All P0.05). Macrophages infiltration in adipose tissue in high fat diet mice gradually increased with time,coincident with decrease in Treg numbers. Increased numbers of Treg,improved metabolic parameters,and decreased ratio of M1/M2 can be seen after rapamycin intervention in mice.Conclusion The decrease of Tregs in the early stage of obesity may contribute to abnormal distribution of macrophage subtypes in visceral adipose.

Room-temperature ionic liquids are new emerging green material. They have good chemical and thermal stability, negligible vapor pressure, nonflammability, high ionic conductivity, transparence, and a wide electrochemical window. So the ionic liquid material strongly tempts many researchers. But ionic liquids are usually applied in chemistry and rarely applied in physics. In fact ionic liquids are good photoelectric medium material owing to its well ionic conductivity, transparence. However, in applications, the drive of ionic liquids is the key technic and is also a bottle-neck. Here a kind of electromagnetic drive way is presented, There are not any mechanical moving elements and the drive is bidirectional. Theory and experiments indicate the drive pressure and flow rate are distinct undering a few voltages and 0.5T magnetic flux density. So this drive way can be used as a low power liquid pump. Latency applications in Microfluidics, Optoelectronics and industry are given.

Osteogenesis imperfect (OI) is a heritable connective tissue disorder with bone fragility as a cardinal manifestation, accompanied by short stature, dentinogenesis imperfecta, hyperlaxity of ligaments and skin, blue sclerae and hearing loss. Dominant form of OI is caused by mutations in the type I procollagen genes, COL1A1/A2. Here we identified a novel splicing mutation c.3207+1G>A (GenBank ID: JQ236861) in the COL1A1 gene that caused type I OI in a Chinese family. RNA splicing analysis proved that this mutation created a new splicing site at c.3200, and then led to frameshift. This result further enriched the mutation spectrum of type I procollagen genes.

Sperm and eggs carry distinctive epigenetic modifications that are adjusted by reprogramming after fertilization. The paternal genome in a zygote undergoes active DNA demethylation before the first mitosis. The biological significance and mechanisms of this paternal epigenome remodelling have remained unclear. Here we report that, within mouse zygotes, oxidation of 5-methylcytosine (5mC) occurs on the paternal genome, changing 5mC into 5-hydroxymethylcytosine (5hmC). Furthermore, we demonstrate that the dioxygenase Tet3 (ref. 5) is enriched specifically in the male pronucleus. In Tet3-deficient zygotes from conditional knockout mice, paternal-genome conversion of 5mC into 5hmC fails to occur and the level of 5mC remains constant. Deficiency of Tet3 also impedes the demethylation process of the paternal Oct4 and Nanog genes and delays the subsequent activation of a paternally derived Oct4 transgene in early embryos. Female mice depleted of Tet3 in the germ line show severely reduced fecundity and their heterozygous mutant offspring lacking maternal Tet3 suffer an increased incidence of developmental failure. Oocytes lacking Tet3 also seem to have a reduced ability to reprogram the injected nuclei from somatic cells. Therefore, Tet3-mediated DNA hydroxylation is involved in epigenetic reprogramming of the zygotic paternal DNA following natural fertilization and may also contribute to somatic cell nuclear reprogramming during animal cloning.

The post-fire behavior of a set of ceramsite concrete filled steel tubes (note as CCST) after exposure to fire are experimentally studied. Effect of the maximum value of fire response temperatures of the tubes and their geometric parameters on the strength and ductility of the specimens were especially discussed. The test results show that the specimens of CCST have higher post-fire bearing capacity and better ductility, there was no obvious descent segment in post-fire load-displacement curves of the most specimens subjected to fire load. It was concluded that the maximum response temperature of specimens has great effect on the post-fire bearing capacity of concrete-filled steel tubes subjected to fire load.

A kind of FGD gypsum from Ningbo Beilun Power Plant of China and fly ash were used as the raw materials with which a complex cementing material was made. Effect of the related factors such as water proportion, mineral admixtures and chemical activators on characteristics of Hemi-hydrate FGD gypsum-fly ash complex cementing material is studied through a number of single factor experiments. The experimental results show that an appropriate amount of admixtures can effectively improve the strength of the Hemi-hydrate FGD gypsum–fly ash complex cementing material presented here. It is concluded that the strength of HFGD-FACM is best as the ratio of HFGD gypsum and fly ash is 1:1 and proper water aggregate proportion is 0.45~0.50.

The computational model of numerical analysis of a suspended pre-stressed steel reticulated shell subjected to fire load is established with using the software Marc. Based on the model presented here, numerical analysis of thermal response and structural response of the pre-stressed steel structure are computed for the key nodes of the structure. The different location of fire source and different space height are considered for analysis of response temperature, displacements and stresses of the pre-stressed lattice shell. It is shown that the air temperatures was much higher than the response temperatures of the nodes of the lattice shell during a quite period of time after a fire takes place, and the temperature of the cable nodes are also less than the air temperature near the nodes. It is also concluded that displacement of the node right above the inner cable is the maximum among the four nodes as the fire source is located at the position under the middle cable.

The computational model of numerical analysis of a suspended pre-stressed steel reticulated shell subjected to fire load is established with using the software Marc. Based on the model presented here, numerical analysis of thermal response and structural response of the pre-stressed steel structure are computed. The different space height and different rise-span ratio are considered for analysis of response temperature, displacements and stresses of the pre-stressed lattice shell under fire for one fire source. It is also shown that displacement of the node right above the inner cable is the maximum among the four nodes presented here as the fire source is located at the position right below the second-ring cable of the structure. It is concluded that the influence degree of space height of the structure on the fire response of the structure is not great, but rise-span ratio has obvious and great effect on displacements and stresses of the pre-stressed steel structure with large span in fire.

Numerical analysis of thermal response and structural response of a suspended pre-stressed steel reticulated lattice shell are conducted for the key nodes of the structure of a gymnasium on software FDS. Two different location of fire source are considered for analysis of response displacements and stresses of the nodes of the pre-stressed lattice shell and three cables. It is shown that the response temperatures of three cables set in the structure have similar variation trend for the fire scene presented here and the fire temperature near inner cable is highest among the three cables. It is concluded that the shell element of center of the structure has largest response stress, and the element above the side cable has larger stress than the shell element above the middle cable when the fire source is located at center of the gymnasium. It is shown that decrease of the pre-stress of the outer cable far away from the fire source is smallest among the three cables set in the structure.

The numerical model for analysis of fire behavior of the spatial pre-stressed steel structure is established based on the software Marc. Analysis of thermal response and structural response of a suspended pre-stressed steel reticulated lattice shell are computed for the key nodes of the structure. For comparison, the air temperatures near the key nodes are also calculated based on the practical formula of large space air temperature rise. The different location of fire source is considered for analysis of response temperature, displacements and stresses of the nodes of the pre-stressed lattice shell. It is shown that the air temperatures obtained from the practical formula was always higher than the response temperatures of the nodes of the lattice shell during a quite long time after a fire takes place. The results show that the displacement of the node near the center of the gymnasium in fire is close to that of the node right above the inner cable, and the displacement of the node right above the outer cable is much less than the result of the center node.

In order to study the fire behavior of the profiled sheet-ceramsite concrete composite floor subjected to fire load, research on fire response and post-fire bearing capacity of a profiled sheet-ceramsite concrete composite floor subjected to dead load, which has no shearing nails, is carried out here through experiment. Based on the experimental results, the fire behavior and post-fire bearing capacity of the floor after exposure to fire are analyzed. It is shown that the failure form of the profiled sheet-ceramsite concrete composite floor after exposure to fire has obvious change compared with the floor not subjected to fire load, but the composite floor subjected to fire still exhibits higher bending capacity, and the ultimate value of the equivalent distributed load is up to 35kN/m2, which may be used as basis of strengthening and repairing of the profiled sheet-ceramsite concrete composite floor after exposure to fire.

In order to study the fire-resistance behavior of the spatial pre-stressed steel structures with large span, the model of numerical analysis of a suspended pre-stressed steel reticulated shell subjected to fire load is established with using the software Marc. Based on the model presented here, numerical analysis of thermal response and structural response of the pre-stressed steel structure are computed for the key nodes of the structure. For comparison, the air temperatures near the key nodes are also calculated based on the practical formula of large space air temperature rise. The different location of fire source is considered for analysis of response temperature, displacements and stresses of the nodes of the pre-stressed lattice shell. It is shown that the air temperatures was much higher than the response temperatures of the nodes of the lattice shell during a quite period of time after a fire takes place, and the temperature of the cable nodes are also less than the air temperature near the nodes. It is also concluded that not the cable nearest the fire source but the other cables around the cable fail to work first in the fire.

Mechanical behavior of a set of ordinary concrete filled steel tubular short column (note as NCSSC) and ceramsite concrete filled steel tubular short column (note as CCSSC) subjected to fire load are experimentally investigated. Effect of the parameters, such as the maximum value of fire temperatures, fire duration on the strength and ductility of the two types of specimens were especially discussed. The test results show that both of the specimens of NCSSC and CCSSC have higher post-fire bearing capacity and better ductility, there was no descent segment in post-fire load-displacement curves of the most specimens subjected to fire load. It was concluded that the maximum response temperature of specimens and fire duration time has great effect on the axial bearing capacity of concrete-filled steel tubular short columns subjected to fire. The maximum longitudinal strain of specimens of CCSSC is less than the corresponding value of the longitudinal strain of NCSSC.

The fire experiment was conducted for three of circular steel tubes protected with two different gypsum fireproof panel and the steel tube without any protective material. The fire response temperature of surface of steel tubes was measured and the axial compressive bearing capacity of the specimens after fire were tested and analyzed. The test results show that gypsum fireproof panel has better fire protection characteristics. It is noted that the variation of temperatures of inner surface of gypsum fireproof panel under fire is consistent with the temperature of outer surface of the steel tube. The maximum difference of temperature between the outer surface of the tube and the furnace space is 150°C as the fire keeps stable for the steel tube without any protection. It is concluded that two of the specimens protected with gypsum fireproof panel have larger post-fire capacity, which means that the gypsum fireproof panel has better effect on fireproof of the steel tube under fire.

To localize the pathogenic genes of autosomal dominant ichthyosis vulgaris, we ascertained two ichthyosis vulgaris families from Hunan Province. Venous blood samples were collected from affected and unaffected family members and genomic DNA was extracted. We then performed genome scan and linkage analysis using microsatellite markers around known ichthyosis vulgaris loci in chromosomes 1 and 10. In family 1, the locus linked to ichthyosis vulgaris was located near D1S498 (1q21), which overlapped with known ichthyosis vulgaris loci. In family 2, however, all known loci for ichthyosis vulgaris were excluded and the new locus remains to be identified.

Background Familial hypercholesterolemia (FH) is a type of dominant autosomal disease that causes high levels of plasma low-density lipoprotein cholesterol(LDL-C).In the past years,molecular data related to FH were limited in China. Now,to gain more information about FH,we analyzed one proband with a severe FH phenotype as well as his relatives. Methods After the entire coding sequence and the intron-exon junctions of the low-density lipoprotein receptor (LDLR) gene were amplified using PCR,we sequenced the LDLR gene of a Chinese FH family.RT-PCR was used to detect changes in the mRNA. Results Two novel mutations were identified in the LDLR gene of this family.One,W165X,was a GA substitution at the third nucleotide of codon 165.The other,IVS5-1GA,was also a GA substitution at the acceptor splice site of intron 5.The most striking discovery is that the proband was heterozygous for W165X but homozygous for IVS5-1GA.The cDNA sequencing showed that the IVS5-1GA mutation caused the insertion of 10 nucleotides,namely GCTCTCACAA, between exon 5 and exon 6. Conclusions The two nucleotide variations are thought to be the FH-causing mutations because the co-segregation of the mutant allele with the phenotype of FH has been shown in this Chinese family.These data show an increase in the mutational spectrum of FH in China and verify a scarce mutational form in the LDLR gene. Chin Med J 2007;120(19):1694-1699

To investigate the effect of high-fat or high-glucose diet on obesity and visceral adipose tissue in C57BL/6 mice.Four-week-old C57BL/6 mice were allocated into normal diet group,high-fat diet group,and high-glucose diet group according to the random number table until 20 weeks old. Body weight,epididymal adipose tissue weight,blood leptin,fat infiltration in liver,M1/M2 macrophage subtypes,and monocyte chemoattractant protein-1 mRNA in epididymal adipose tissues were measured.Compared with normal diet group,body weight,epididymal adipose tissue weight,and leptin concentration in high fat diet group at 20 weeks were significantly increased (P0.05),and oil red O staining showed more prominent adipocyte infiltration in liver in high-fat diet group than those in normal diet and high-glucose diet group. However,no apparent differences were seen in high-glucose diet group at 20 weeks in terms of body weight,epididymal adipose tissue weight and leptin concentration. In high-fat diet group,the macrophages infiltration in epididymal adipose tissue increased with time and the percentage of M2 macrophage decreased in high-fat diet group than that in high-glucose diet group(P0.05). Compared with normal diet group,monocyte chemoattractant protein-1 mRNA expression increased significantly in high-fat diet group(P0.05). In high-glucose group,however,no significant differences were discerned (P0.05).High-fat diet,rather than 60% high glucose diet,will lead to obesity and macrophage infiltration in adipose tissues.

Piebaldism is a rare autosomal dominant disorder of melanocyte development, which is mostly caused byKITgene. The key characteristics of piebaldism include localized poliosis, congenital leukoderma, and other variable manifestations. The previous study has illustrated that the homogeneousMC1R(a gene which is associated with the hair color) variant (p.I120T) coordinating withKITmutation may lead to auburn hair color and piebaldism. In this study, we have investigated a Chinese family with piebaldism and auburn hair color; the mutation screening ofKITandMC1Rgenes identified that only a splicing mutation (c. 2484+1G>A) ofKITgene cosegregated with the auburn hair color and piebaldism. The data of this study and others suggests that the KIT mutation may causes of the auburn hair color in the piebaldism patients.

Loss-of-function mutations in filaggrin gene (FLG; OMIM #135940) have been reported to cause the semi-dominant keratinizing disorders such as ichthyosis vulgaris (IV; OMIM #146700) and atopic dermatitis (AD; OMIM #605803). Recent linkage analysis and immunohistochemical studies suggest the possible contribution of FLG to psoriatic susceptibility. However, no susceptibility variant in FLG gene associated with psoriasis (OMIM #177900) has been identified. In this study, we identified a non-sense mutation of FLG (p.K4022X) in a Chinese psoriasis/IV coexisting family. The homozygous p.K4022X mutation was detected in a psoriasis patient, whereas the heterozygous p.K4022X mutation was identified in two IV patients and four apparently normal family members. We also genotyped p.K4022X variant in 441 sporadic Chinese psoriasis patients and found homozygous mutation in two patients, while no homozygous variant was found in 500 control individuals. After sequencing the entire coding region of FLG gene in 441 psoriasis patients, we identified another five mutations (p.R826X, p.W2583X, c.7945delA, c.3321delA and p.Q2417X). Although all six FLG mutations as a whole was not significantly associated with psoriasis (P = 0.105), mutation p.K4022X was significantly associated with psoriasis (P < 0.05). Our data thus indicates an association of FLG with psoriasis in Chinese population.

Waardenburg syndrome (WS) is a rare disorder characterized by distinctive facial features, pigment disturbances, and sensorineural deafness. There are four WS subtypes. WS1 is mostly caused by PAX3 mutations, while MITF, SNAI2, and SOX10 mutations are associated with WS2. More than 100 different disease-causing mutations have been reported in many ethnic groups, but the data from Chinese patients with WS remains poor. Herein we report 18 patients from 15 Chinese WS families, in which five cases were diagnosed as WS1 and the remaining as WS2. Clinical evaluation revealed intense phenotypic variability in Chinese WS patients. Heterochromia iridis and sensorineural hearing loss were the most frequent features (100% and 88.9%, respectively) of the two subtypes. Many brown freckles on normal skin could be a special subtype of cutaneous pigment disturbances in Chinese WS patients. PAX3, MITF, SNAI2, and SOX10 genes mutations were screened for in all the patients. A total of nine mutations in 11 families were identified and seven of them were novel. The SOX10 mutations in WS2 were first discovered in the Chinese population, with an estimated frequency similar to that of MITF mutations, implying SOX10 is an important pathogenic gene in Chinese WS2 cases and should be considered for first-step analysis in WS2, as well as MITF.

To localize the pathogenic genes of autosomal dominant ichthyosis vulgaris, we ascertained two ichthyosis vulgaris families from Hunan Province. Venous blood samples were collected from affected and unaffected family members and genomic DNA was extracted. We then performed genome scan and linkage analysis using microsatellite markers around known ichthyosis vulgaris loci in chromosomes 1 and 10. In family 1, the locus linked to ichthyosis vulgaris was located near D1S498 (1q21), which overlapped with known ichthyosis vulgaris loci. In family 2, however, all known loci for ichthyosis vulgaris were excluded and the new locus remains to be identified.

To identify the MLH1 and MSH2 gene mutation in two hereditary nonpolyposis colorectal cancer (HNPCC) families.Polymerase chain reaction and DNA sequencing were used to screen for MLH1 and MSH2 gene mutation, and PCR-restriction fragment length polymorphism and DNA sequencing were performed to confirm the mutation.By DNA sequencing, a novel mutation of c.243_244insA located at the exon 3 of MLH1 gene was detected in family A, while c.1215_1218dupCCGA mutation located at the exon 7 of MSH2 gene was detected in family B. These two mutations can cause the formation of premature proteins.The novel mutations c.243_244insA in MLH1 gene and c.1215_1218dupCCGA in MSH2 gene were the disease-causing mutations in the two HNPCC families.

To explore the disease associated gene mutation of multiple exostoses by family analysis.Polymerase chain reaction and DNA sequencing were used to detect the mutation hot spot regions of EXT1 and EXT2 gene, while restriction fragment length polymorphism was performed to screen the mutation.We found a novel heterozygous mutation c.811T -C in EXT1 gene of patients, which resulted in the substitution of histidine for tyrosine at codon 271 in this hereditary multiple exostoses family. The mutation was not found in the unaffected family members, nor in the 100 unrelated normal individual, which was unreported before.The novel mutation Y271H is the disease-causing mutation in the hereditary multiple exostoses family.

To elucidate the pathogenic genes in a pedigree with autosomal dominant ichthyosis vulgaris (IV).Linkage analysis was performed by using STR markers in chromosome 1, and mutation detection was used to screen for FLG gene mutation.A maximum two-point Lod score of 3.46 (theta=0) was obtained at D1S2696. Haplotype analysis placed the critical region in a 15-CM interval defined by D1S2726 and D1S305, but no mutation of FLG was found in our IV patients.The pathologic gene of the IV family locates near D1S2696, and the FLG gene may not ruled out from the pathologic genes.

To detect mutations of guanosine triphosphate cyclohydrolase I (GCH1) gene in Chinese patients with dopa responsive dystonia (DRD).Six sporadic patients with DRD were examined. GCH1 gene mutations were detected using polymerase chain reaction (PCR), DNA sequence analysis and restriction enzyme digestion analysis. One hundred normal people were detected using PCR and restriction enzyme digestion analysis.A new point mutation, 151(G--A) in exon one was found in a patient. It lead to substitution of a methionine for isoleucine at amino acid 1(M1I). This mutation was not found in normal control people.The authors report a new heterozygotic point mutation 151(G--A) in GCH1 gene. There are GCH1 gene mutations in Chinese sporadic patients with DRD.

To study the clinical and genetic characteristics of a Chinese family with benign familial convulsions (BFNC).The clinical data of this family was analyzed. The blood samples were collected from 13 members of this family. By four microsatellite markers which are located in the gene loci of both K+ channel KCNQ2 and KCNQ3, the linkage analysis was performed in the family. With DNA direct sequencing and restriction endonuclease cutting analysis, the mutation analysis of KCNQ3 gene was made for the proband, other 12 family members and 76 unrelated normal individuals.There were 7 patients with BFNC observed in the three generation of family. The BFNC seizures of all patients disappeared during one month and no recurrence of seizures was found. The linkage analysis suggested the disease gene linked to KCNQ3 gene locus in the family. The mutation 988(C to T) of KCNQ3 gene was found in the proband by DNA-direct sequencing. Cosegregation of this mutation with BFNC was confirmed by restriction endonuclease cutting analysis.Chinese patients with BFNC can be caused by KCNQ3 gene mutation.

To study the gene mutation in a patient with multiple exostoses, identify the disease-causing gene mutation.Polymerase chain reaction and DNA sequencing were used to screen the EXT1 or EXT2 gene mutation, while mismatch primer amplification and restriction endonuclease digestion were performed to confirm the mutation.By DNA sequencing, a mutation in the seventh intron was detected and located at 26 bp of 3' splice site upstream in EXT1 gene, which was unreported before. Mismatch primer amplification and restriction fragment length polymorphism analysis suggested that this mutation was not detected in the normal control.The mutation 1633-26(C--A) may be the disease-causing mutation in this patient with multiple exostoses.