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[
{
"name": "VHL",
"pos": [
10,
13
],
"type": "Disease"
},
{
"name": "tumors",
"pos": [
59,
65
],
"type": "Disease"
}
] | A somatic VHL gene mutation was detected in one of the two tumors by polymerase chain reaction followed by single - strand conformation polymorphism analysis . |
[] | Direct sequencing revealed a cytosine to thymine transition at nucleotide 694 , resulting in the replacement of an arginine with a stop codon after the sixth amino acid of exon 3 . |
[
{
"name": "VHL",
"pos": [
7,
10
],
"type": "Disease"
},
{
"name": "tumor",
"pos": [
45,
50
],
"type": "Disease"
},
{
"name": "VHL",
"pos": [
69,
72
],
"type": "Disease"
},
{
"name": "cystadenomas of the epididymis",
"pos": [
151,
181
],
"type": "Disease"
}
] | As the VHL gene is believed to function as a tumor suppressor gene , VHL gene mutations may play a role in the initiation of tumorigenesis in sporadic cystadenomas of the epididymis . |
[
{
"name": "Wiskott - Aldrich syndrome",
"pos": [
50,
76
],
"type": "Disease"
},
{
"name": "isolated thrombocytopenia",
"pos": [
81,
106
],
"type": "Disease"
},
{
"name": "WAS",
"pos": [
144,
147
],
"type": "Disease"
}
] | Identification of WASP mutations in patients with Wiskott - Aldrich syndrome and isolated thrombocytopenia reveals allelic heterogeneity at the WAS locus . |
[
{
"name": "genetic defect",
"pos": [
96,
110
],
"type": "Disease"
},
{
"name": "X - linked Wiskott - Aldrich syndrome",
"pos": [
131,
168
],
"type": "Disease"
},
{
"name": "WAS",
"pos": [
171,
174
],
"type": "Disease"
},
{
"name": "immunodeficiency disease",
"pos": [
189,
213
],
"type": "Disease"
}
] | Mutation in the gene encoding the recently isolated WASP protein has now been identified as the genetic defect responsible for the X - linked Wiskott - Aldrich syndrome ( WAS ) , a primary immunodeficiency disease associated with extensive phenotypic variability . |
[
{
"name": "WAS",
"pos": [
26,
29
],
"type": "Disease"
},
{
"name": "WAS",
"pos": [
57,
60
],
"type": "Disease"
},
{
"name": "isolated thrombocytopenia",
"pos": [
198,
223
],
"type": "Disease"
}
] | To elucidate the range of WASP mutations responsible for WAS , we used PCR - SSCP analysis to screen for WASP gene mutation in 19 unrelated boys with the diagnosis of classical or attenuated WAS or isolated thrombocytopenia . |
[] | All 19 patients had WASP mutations , each of which localized to the initial three or terminal three exons of the gene , and the majority of which were unique in each case . |
[
{
"name": "WAS",
"pos": [
79,
82
],
"type": "Disease"
},
{
"name": "WAS",
"pos": [
133,
136
],
"type": "Disease"
},
{
"name": "thrombocytopenia",
"pos": [
175,
191
],
"type": "Disease"
}
] | However , a missense mutation which results in substitution of the arginine at WAS codon 86 was identified in three boys with severe WAS as well as in one boy presenting with thrombocytopenia alone . |
[
{
"name": "isolated thrombocytopenia",
"pos": [
39,
64
],
"type": "Disease"
},
{
"name": "WAS",
"pos": [
187,
190
],
"type": "Disease"
}
] | While the three mutations found in the isolated thrombocytopenia patients leave the reading frame intact , about one - half of the gene alterations detected in both severe and attenuated WAS patients result in frameshifted transcript and premature translation termination . |
[
{
"name": "WAS",
"pos": [
52,
55
],
"type": "Disease"
},
{
"name": "congenital thrombocytopenia",
"pos": [
126,
153
],
"type": "Disease"
}
] | These findings therefore confirm the association of WAS with WASP mutation and identify WASP mutation as a cause for isolated congenital thrombocytopenia in males . |
[
{
"name": "isolated thrombocytopenia",
"pos": [
44,
69
],
"type": "Disease"
},
{
"name": "WAS",
"pos": [
102,
105
],
"type": "Disease"
},
{
"name": "WAS",
"pos": [
160,
163
],
"type": "Disease"
},
{
"name": "WAS",
"pos": [
203,
206
],
"type": "Disease"
},
{
"name": "isolated thrombocytopenia",
"pos": [
324,
349
],
"type": "Disease"
},
{
"name": "WAS",
"pos": [
378,
381
],
"type": "Disease"
}
] | While the WASP gene defects responsible for isolated thrombocytopenia and other mild presentations of WAS do not appear distinct from those resulting in severe WAS , these data indicate that analysis of WASP gene mutation provides a valuable tool for distinguishing the spectrum of WAS patients and the subset of males with isolated thrombocytopenia who represent mild cases of WAS . . |
[
{
"name": "Wiskott - Aldrich syndrome",
"pos": [
23,
49
],
"type": "Disease"
},
{
"name": "X - linked thrombocytopenia",
"pos": [
54,
81
],
"type": "Disease"
}
] | WASP gene mutations in Wiskott - Aldrich syndrome and X - linked thrombocytopenia . |
[] | The WASP gene has been recently cloned from Xp11 . |
[
{
"name": "Wiskott - Aldrich syndrome",
"pos": [
54,
80
],
"type": "Disease"
},
{
"name": "WAS",
"pos": [
83,
86
],
"type": "Disease"
}
] | 23 and shown to be mutated in three patients with the Wiskott - Aldrich syndrome ( WAS ) . |
[] | We have developed a screening protocol for identifying WASP gene alterations in genomic DNA and have identified a spectrum of novel mutations in 12 additional unrelated families . |
[] | These missense , nonsense and frameshift mutations involve eight of the 12 exons of the gene . |
[] | Two mutations creating premature termination codons were associated with lack of detectable mRNA on Northern blots . |
[
{
"name": "congenital thrombocytopenia",
"pos": [
107,
134
],
"type": "Disease"
},
{
"name": "X - linked thrombocytopenia",
"pos": [
234,
261
],
"type": "Disease"
},
{
"name": "WAS",
"pos": [
276,
279
],
"type": "Disease"
}
] | Four amino acid substitutions , Leu27Phe , Thr48Ile , Val75Met and Arg477Lys , were found in patients with congenital thrombocytopenia and no clinically evident immune defect indicating that the WASP gene is the site for mutations in X - linked thrombocytopenia as well as in WAS . |
[
{
"name": "WAS",
"pos": [
23,
26
],
"type": "Disease"
}
] | A T - cell line from a WAS patient contained two independent DNA alterations , a constitutional frameshift mutation , also present in peripheral blood leukocytes from the patient , and compensatory splice site mutation unique to the cell line . |
[] | The distribution of eight missense mutations provides valuable information on amino acids which are essential for normal protein function , and suggests that sites in the first two exons are hot - spots for mutation . |
[
{
"name": "Machado - Joseph disease",
"pos": [
175,
199
],
"type": "Disease"
}
] | Evidence for inter - generational instability in the CAG repeat in the MJD1 gene and for conserved haplotypes at flanking markers amongst Japanese and Caucasian subjects with Machado - Joseph disease . |
[
{
"name": "Machado - Joseph disease",
"pos": [
234,
258
],
"type": "Disease"
},
{
"name": "MJD",
"pos": [
261,
264
],
"type": "Disease"
}
] | The size of the ( CAG ) n repeat array in the 3 ' end of the MJD1 gene and the haplotype at a series of microsatellite markers surrounding the MJD1 gene were examined in a large cohort of Japanese and Caucasian subjects affected with Machado - Joseph disease ( MJD ) . |
[] | Our data provide five novel observations . |
[
{
"name": "MJD",
"pos": [
8,
11
],
"type": "Disease"
},
{
"name": "MJD",
"pos": [
255,
258
],
"type": "Disease"
}
] | First , MJD is associated with expansion fo the array from the normal range of 14 - 37 repeats to 68 - 84 repeats in most Japanese and Caucasian subjects , but no subjects were observed with expansions intermediate in size between those of the normal and MJD affected groups . |
[
{
"name": "MJD",
"pos": [
45,
48
],
"type": "Disease"
}
] | Second , the expanded allele associated with MJD displays inter - generational instability , particularly in male meioses , and this instability was associated with the clinical phenomenon of anticipation . |
[
{
"name": "MJD",
"pos": [
102,
105
],
"type": "Disease"
}
] | Third , the size of the expanded allele is not only inversely correlated with the age - of - onset of MJD ( r = - 0 . 738 , p < 0 . 001 ) , but is also correlated with the frequency of other clinical features [ e . g . pseudoexophthalmos and pyramidal signs were more frequent in subjects with large repeats ( p < 0 . 001 and p < 0 . 05 respectively ) ] . |
[
{
"name": "Huntington disease",
"pos": [
174,
192
],
"type": "Disease"
},
{
"name": "HD",
"pos": [
333,
335
],
"type": "Disease"
},
{
"name": "HD",
"pos": [
386,
388
],
"type": "Disease"
}
] | Fourth , the disease phenotype is significantly more severe and had an early age of onset ( 16 years ) in a subject homozygous for the expanded allele , which contrasts with Huntington disease and suggests that the expanded allele in the MJD1 gene could exert its effect either by a dominant negative effect ( putatively excluded in HD ) or by a gain of function effect as proposed for HD . |
[
{
"name": "MJD",
"pos": [
56,
59
],
"type": "Disease"
}
] | Finally , Japanese and Caucasian subjects affected with MJD share haplotypes at several markers surrounding the MJD1 gene , which are uncommon in the normal Japanese and Caucasian population , and which suggests the existence either of common founders in these populations or of chromosomes susceptible to pathologic expansion of the CAG repeat in the MJD1 gene . |
[
{
"name": "Machado - Joseph disease",
"pos": [
175,
199
],
"type": "Disease"
}
] | Evidence for inter - generational instability in the CAG repeat in the MJD1 gene and for conserved haplotypes at flanking markers amongst Japanese and Caucasian subjects with Machado - Joseph disease . |
[
{
"name": "Machado - Joseph disease",
"pos": [
234,
258
],
"type": "Disease"
},
{
"name": "MJD",
"pos": [
261,
264
],
"type": "Disease"
}
] | The size of the ( CAG ) n repeat array in the 3 ' end of the MJD1 gene and the haplotype at a series of microsatellite markers surrounding the MJD1 gene were examined in a large cohort of Japanese and Caucasian subjects affected with Machado - Joseph disease ( MJD ) . |
[] | Our data provide five novel observations . |
[
{
"name": "MJD",
"pos": [
8,
11
],
"type": "Disease"
},
{
"name": "MJD",
"pos": [
255,
258
],
"type": "Disease"
}
] | First , MJD is associated with expansion fo the array from the normal range of 14 - 37 repeats to 68 - 84 repeats in most Japanese and Caucasian subjects , but no subjects were observed with expansions intermediate in size between those of the normal and MJD affected groups . |
[
{
"name": "MJD",
"pos": [
45,
48
],
"type": "Disease"
}
] | Second , the expanded allele associated with MJD displays inter - generational instability , particularly in male meioses , and this instability was associated with the clinical phenomenon of anticipation . |
[
{
"name": "MJD",
"pos": [
102,
105
],
"type": "Disease"
}
] | Third , the size of the expanded allele is not only inversely correlated with the age - of - onset of MJD ( r = - 0 . 738 , p < 0 . 001 ) , but is also correlated with the frequency of other clinical features [ e . g . pseudoexophthalmos and pyramidal signs were more frequent in subjects with large repeats ( p < 0 . 001 and p < 0 . 05 respectively ) ] . |
[
{
"name": "Huntington disease",
"pos": [
174,
192
],
"type": "Disease"
},
{
"name": "HD",
"pos": [
333,
335
],
"type": "Disease"
},
{
"name": "HD",
"pos": [
386,
388
],
"type": "Disease"
}
] | Fourth , the disease phenotype is significantly more severe and had an early age of onset ( 16 years ) in a subject homozygous for the expanded allele , which contrasts with Huntington disease and suggests that the expanded allele in the MJD1 gene could exert its effect either by a dominant negative effect ( putatively excluded in HD ) or by a gain of function effect as proposed for HD . |
[
{
"name": "MJD",
"pos": [
56,
59
],
"type": "Disease"
}
] | Finally , Japanese and Caucasian subjects affected with MJD share haplotypes at several markers surrounding the MJD1 gene , which are uncommon in the normal Japanese and Caucasian population , and which suggests the existence either of common founders in these populations or of chromosomes susceptible to pathologic expansion of the CAG repeat in the MJD1 gene . |
[
{
"name": "Langer - Giedion syndrome",
"pos": [
41,
66
],
"type": "Disease"
},
{
"name": "trichorhinophalangeal syndrome",
"pos": [
141,
171
],
"type": "Disease"
}
] | A 4 - megabase YAC contig that spans the Langer - Giedion syndrome region on human chromosome 8q24 . 1 : use in refining the location of the trichorhinophalangeal syndrome and multiple exostoses genes ( TRPS1 and EXT1 ) . |
[] | We have constructed a physical map covering over 4 Mb of human chromosome 8q24 . |
[
{
"name": "Langer - Giedion syndrome",
"pos": [
73,
98
],
"type": "Disease"
}
] | 1 and used this map to refine the locations of the genes responsible for Langer - Giedion syndrome . |
[] | The map is composed of overlapping YAC clones that were identified and ordered in relation to sequence tagged sites mapped to the Langer - Giedion chromosomal region on somatic cell hybrids . |
[
{
"name": "Langer - Giedion syndrome",
"pos": [
33,
58
],
"type": "Disease"
}
] | The minimal region of overlap of Langer - Giedion syndrome deletions , previously identified by analysis of 15 patients , was placed on the map by analysis of 2 patients whose deletions define the endpoints . |
[
{
"name": "trichorhinophalangeal syndrome",
"pos": [
111,
141
],
"type": "Disease"
},
{
"name": "TRPS",
"pos": [
144,
148
],
"type": "Disease"
}
] | The chromosome 8 breakpoint of a balanced t ( 8 ; 9 ) ( q24 . 11 ; q33 . 3 ) translocation from a patient with trichorhinophalangeal syndrome ( TRPS I ) was found to be located just within the proximal end of the minimal deletion region . |
[] | A deletion of 8q24 . |
[] | 11 - q24 . |
[
{
"name": "LGS",
"pos": [
82,
85
],
"type": "Disease"
},
{
"name": "Langer - Giedion syndrome",
"pos": [
197,
222
],
"type": "Disease"
}
] | 3 in a patient with multiple exostoses was found to overlap the distal end of the LGS deletion region , indicating that the EXT1 gene is distal to the TRPS1 gene and supporting the hypothesis that Langer - Giedion syndrome is due to loss of functional copies of both the TRPS1 and the EXT1 genes |
[
{
"name": "breast cancer",
"pos": [
67,
80
],
"type": "Disease"
}
] | BRCA1 mutations in a population - based sample of young women with breast cancer . |
[] | BACKGROUND . |
[
{
"name": "breast and ovarian cancer",
"pos": [
73,
98
],
"type": "Disease"
}
] | Inherited mutations in the BRCA1 gene are associated with a high risk of breast and ovarian cancer in some families . |
[
{
"name": "breast cancer",
"pos": [
71,
84
],
"type": "Disease"
}
] | However , little is known about the contribution of BRCA1 mutations to breast cancer in the general population . |
[
{
"name": "breast cancer",
"pos": [
91,
104
],
"type": "Disease"
},
{
"name": "breast cancer",
"pos": [
193,
206
],
"type": "Disease"
}
] | We analyzed DNA samples from women enrolled in a population - based study of early - onset breast cancer to assess the spectrum and frequency of germ - line BRCA1 mutations in young women with breast cancer . |
[] | METHODS . |
[
{
"name": "breast cancer",
"pos": [
28,
41
],
"type": "Disease"
}
] | We studied 80 women in whom breast cancer was diagnosed before the age of 35 , and who were not selected on the basis of family history . |
[] | Genomic DNA was studied for BRCA1 mutations by analysis involving single - strand conformation polymorphisms and with allele - specific assays . |
[] | Alterations were defined by DNA sequencing . |
[] | RESULTS . |
[] | Germ - line BRCA1 mutations were identified in 6 of the 80 women . |
[] | Four additional rare sequence variants of unknown functional importance were also identified . |
[
{
"name": "breast or ovarian cancer",
"pos": [
125,
149
],
"type": "Disease"
}
] | Two of the mutations and three of the rare sequence variants were found among the 39 women who reported no family history of breast or ovarian cancer . |
[] | None of the mutations and only one of the rare variants was identified in a reference population of 73 unrelated subjects . |
[] | CONCLUSIONS . |
[
{
"name": "breast cancer",
"pos": [
100,
113
],
"type": "Disease"
}
] | Alterations in BRCA1 were identified in approximately 10 percent of this cohort of young women with breast cancer . |
[
{
"name": "breast or ovarian cancer",
"pos": [
83,
107
],
"type": "Disease"
}
] | The risk of harboring a mutation was not limited to women with family histories of breast or ovarian cancer . |
[] | These results represent a minimal estimate of the frequency of BRCA1 mutations in this population . |
[] | Comprehensive methods of identifying BRCA1 mutations and understanding their importance will be needed before testing of women in the general population can be undertaken . . |
[] | Novel inherited mutations and variable expressivity of BRCA1 alleles , including the founder mutation 185delAG in Ashkenazi Jewish families . |
[
{
"name": "breast cancer",
"pos": [
51,
64
],
"type": "Disease"
},
{
"name": "breast and ovarian cancer",
"pos": [
68,
93
],
"type": "Disease"
}
] | Thirty - seven families with four or more cases of breast cancer or breast and ovarian cancer were analyzed for mutations in BRCA1 . |
[] | Twelve different germ - line mutations , four novel and eight previously observed , were detected in 16 families . |
[] | Five families of Ashkenazi Jewish descent carried the 185delAG mutation and shared the same haplotype at eight polymorphic markers spanning approximately 850 kb at BRCA1 . |
[
{
"name": "breast cancer",
"pos": [
71,
84
],
"type": "Disease"
},
{
"name": "ovarian cancer",
"pos": [
93,
107
],
"type": "Disease"
}
] | Expressivity of 185delAG in these families varied , from early - onset breast cancer without ovarian cancer . |
[] | Mutation 4184delTCAA occurred independently in two families . |
[
{
"name": "breast cancer",
"pos": [
80,
93
],
"type": "Disease"
},
{
"name": "ovarian cancer",
"pos": [
97,
111
],
"type": "Disease"
},
{
"name": "prostatic cancer",
"pos": [
144,
160
],
"type": "Disease"
},
{
"name": "breast cancer",
"pos": [
230,
243
],
"type": "Disease"
}
] | In one family , penetrance was complete , with females developing early - onset breast cancer or ovarian cancer and the male carrier developing prostatic cancer , whereas , in the other family , penetrance was incomplete and only breast cancer occurred , diagnosed at ages 38 - 81 years . |
[
{
"name": "breast cancer",
"pos": [
121,
134
],
"type": "Disease"
},
{
"name": "ovarian cancer",
"pos": [
139,
153
],
"type": "Disease"
}
] | Two novel nonsense mutations led to the loss of mutant BRCA1 transcript in families with 10 and 6 cases of early - onset breast cancer and ovarian cancer . |
[] | A 665 - nt segment of the BRCA1 3 - UTR and 1 . |
[] | 3 kb of genomic sequence including the putative promoter region were invariant by single - strand conformation analysis in 13 families without coding - sequence mutations . |
[
{
"name": "breast cancers",
"pos": [
168,
182
],
"type": "Disease"
}
] | Overall in our series , BRCA1 mutations have been detected in 26 families 16 with positive BRCA1 lod scores , 7 with negative lod scores ( reflecting multiple sporadic breast cancers ) , and 3 not tested for linkage . |
[] | Three other families have positive lod scores for linkage to BRCA2 , but 13 families without detected BRCA1 mutations have negative lod scores for both BRCA1 and BRCA2 . |
[] | A new glucose - 6 - phosphate dehydrogenase variant , G6PD Orissa ( 44 Ala - - > Gly ) , is the major polymorphic variant in tribal populations in India . |
[
{
"name": "Deficiency of glucose - 6 - phosphate dehydrogenase",
"pos": [
0,
51
],
"type": "Disease"
},
{
"name": "malaria",
"pos": [
126,
133
],
"type": "Disease"
}
] | Deficiency of glucose - 6 - phosphate dehydrogenase ( G6PD ) is usually found at high frequencies in areas of the world where malaria has been endemic . |
[
{
"name": "G6PD deficiency",
"pos": [
35,
50
],
"type": "Disease"
}
] | The frequency and genetic basis of G6PD deficiency have been studied in Africa , around the Mediterranean , and in the Far East , but little such information is available about the situation in India . |
[
{
"name": "G6PD deficiency",
"pos": [
121,
136
],
"type": "Disease"
}
] | To determine the extent of heterogeneity of G6PD , we have studied several different Indian populations by screening for G6PD deficiency , followed by molecular analysis of deficient alleles . |
[
{
"name": "G6PD deficiency",
"pos": [
17,
32
],
"type": "Disease"
}
] | The frequency of G6PD deficiency varies between 3 % and 15 % in different tribal and urban groups . |
[
{
"name": "G6PD deficiency",
"pos": [
123,
138
],
"type": "Disease"
},
{
"name": "G6PD deficiency",
"pos": [
226,
241
],
"type": "Disease"
}
] | Remarkably , a previously unreported deficient variant , G6PD Orissa ( 44 Ala - - > Gly ) , is responsible for most of the G6PD deficiency in tribal Indian populations but is not found in urban populations , where most of the G6PD deficiency is due to the G6PD Mediterranean ( 188 Ser - - > Phe ) variant . |
[] | The KmNADP of G6PD Orissa is fivefold higher than that of the normal enzyme . |
[] | This may be due to the fact that the alanine residue that is replaced by glycine is part of a putative coenzyme - binding site . . |
[
{
"name": "bipolar disorder",
"pos": [
24,
40
],
"type": "Disease"
}
] | Evidence for linkage of bipolar disorder to chromosome 18 with a parent - of - origin effect . |
[
{
"name": "bipolar affective disorder",
"pos": [
97,
123
],
"type": "Disease"
},
{
"name": "BPAD",
"pos": [
126,
130
],
"type": "Disease"
}
] | A susceptibility gene on chromosome 18 and a parent - of - origin effect have been suggested for bipolar affective disorder ( BPAD ) . |
[
{
"name": "BPAD",
"pos": [
88,
92
],
"type": "Disease"
}
] | We have studied 28 nuclear families selected for apparent unilineal transmission of the BPAD phenotype , by using 31 polymorphic markers spanning chromosome 18 . |
[] | Evidence for linkage was tested with affected - sib - pair and LOD score methods under two definitions of the affected phenotype . |
[] | The affected - sibpair analyses indicated excess allele sharing for markers on 18p within the region reported previously . |
[] | The greatest sharing was at D18S37 64 % in bipolar and recurrent unipolar ( RUP ) sib pairs ( P = . 0006 ) . |
[] | In addition , excess sharing of the paternally , but not maternally , transmitted alleles was observed at three markers on 18q at D18S41 , 51 bipolar and RUP sib pairs were concordant for paternally transmitted alleles , and 21 pairs were discordant ( P = 0004 ) . |
[] | The evidence for linkage to loci on both 18p and 18q was strongest in the 11 paternal pedigrees , i . |
[] | e e . , those in which the father or one of the fathers sibs is affected . |
[] | In these pedigrees , the greatest allele sharing ( 81 % ; P = . 00002 ) and the highest LOD score ( 3 . 51 ; phi = 0 . 0 ) were observed at D18S41 . |
[
{
"name": "BPAD",
"pos": [
51,
55
],
"type": "Disease"
}
] | Our results provide further support for linkage of BPAD to chromosome 18 and the first molecular evidence for a parent - of - origin effect operating in this disorder . |
[] | The number of loci involved , and their precise location , require further study |
[
{
"name": "galactosemia",
"pos": [
25,
37
],
"type": "Disease"
}
] | A prevalent mutation for galactosemia among black Americans . |
[
{
"name": "galactosemia",
"pos": [
41,
53
],
"type": "Disease"
}
] | OBJECTIVE To define the mutation causing galactosemia in patients of black American origin who have no galactose - 1 - phosphate uridyltransferase ( GALT ) activity in erythrocytes but good clinical outcome . |
[] | METHODS We discovered a mutation caused by a C - - > T transition at base - pair 1158 of the GALT gene that results in a serine - to - leucine substitution at codon 135 ( S135L ) . |
[] | We developed a method with which to screen populations for its prevalence . |