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[] | Analysis of other affected members of the families showed that , in each case , all affected individuals carried the same family - specific mutation . |
[] | One polymorphism was found in exon 7 . |
[
{
"name": "aniridia",
"pos": [
91,
99
],
"type": "Disease"
}
] | This data strongly supports the candidature of PAX6 as the gene responsible for hereditary aniridia . . |
[
{
"name": "protein S deficiency type I",
"pos": [
65,
92
],
"type": "Disease"
}
] | Three novel mutations in five unrelated subjects with hereditary protein S deficiency type I . |
[
{
"name": "type I protein S deficiency",
"pos": [
51,
78
],
"type": "Disease"
}
] | A panel of eight unrelated subjects with inherited type I protein S deficiency was screened for mutations in the PROS1 gene . |
[] | In five subjects an abnormality was found but mutations were not detected in the remaining three subjects . |
[] | Two subjects shared a G - - > A transition at position + 5 of the donor splice site consensus sequence of intron 10 . |
[] | Also in two subjects an A - - > T transversion was detected in the stopcodon of the PROS1 gene ; this transversion predicts a protein S molecule that is extended by 14 amino acids . |
[] | The fifth subject was found to possess two sequence abnormalities . |
[] | One allele carried a G - - > A transition near the donor splice junction of intron 2 , but this abnormality is probably neutral , since it was inherited from the parent with normal protein S antigen levels . |
[] | In the other allele a single T insertion in codon - 25 was found . |
[] | Analysis of platelet RNA showed that only the mRNA with the A - - > T mutation in the stopcodon is present in amounts comparable to wildtype RNA . |
[] | mRNA from the alleles with the other two mutations was either undetectable or present in greatly reduced amounts . |
[
{
"name": "protein S deficiency type I",
"pos": [
92,
119
],
"type": "Disease"
}
] | The latter indicates that a mRNA based approach is not feasible for the genetic analysis of protein S deficiency type I . . |
[
{
"name": "myotonic dystrophy",
"pos": [
71,
89
],
"type": "Disease"
}
] | Characteristics of intergenerational contractions of the CTG repeat in myotonic dystrophy . |
[
{
"name": "myotonic dystrophy",
"pos": [
3,
21
],
"type": "Disease"
},
{
"name": "DM",
"pos": [
24,
26
],
"type": "Disease"
},
{
"name": "DM",
"pos": [
63,
65
],
"type": "Disease"
}
] | In myotonic dystrophy ( DM ) , the size of a CTG repeat in the DM kinase gene generally increases in successive generations with clinical evidence of anticipation . |
[] | However , there have also been cases with an intergenerational contraction of the repeat . |
[
{
"name": "DM",
"pos": [
20,
22
],
"type": "Disease"
}
] | We examined 1 , 489 DM parent - offspring pairs , of which 95 ( 6 . 4 % ) showed such contractions in peripheral blood leukocytes ( PBL ) . |
[] | In 56 of the 95 pairs , clinical data allowed an analysis of their anticipation status . |
[
{
"name": "DM",
"pos": [
122,
124
],
"type": "Disease"
}
] | It is surprising that anticipation occurred in 27 ( 48 % ) of these 56 pairs , while none clearly showed a later onset of DM in the symptomatic offspring . |
[] | The contraction occurred in 76 ( 10 % ) of 753 paternal transmissions and in 19 ( 3 % ) of 736 maternal transmissions . |
[] | Anticipation was observed more frequently in maternal ( 85 % ) than in paternal ( 37 % ) transmissions ( P < . 001 ) . |
[] | The parental repeat size correlated with the size of intergenerational contraction ( r2 = . 50 , P < < . 001 ) , and the slope of linear regression was steeper in paternal ( - . 62 ) than in maternal ( - . 30 ) transmissions ( P < < . 001 ) . |
[
{
"name": "DM",
"pos": [
8,
10
],
"type": "Disease"
},
{
"name": "DM",
"pos": [
32,
34
],
"type": "Disease"
}
] | Sixteen DM parents had multiple DM offspring with the CTG repeat contractions . |
[
{
"name": "DM",
"pos": [
130,
132
],
"type": "Disease"
},
{
"name": "DM",
"pos": [
157,
159
],
"type": "Disease"
},
{
"name": "DM",
"pos": [
174,
176
],
"type": "Disease"
},
{
"name": "DM",
"pos": [
193,
195
],
"type": "Disease"
}
] | This frequency was higher than the frequency expected from the probability of the repeat contractions ( 6 . 4 % ) and the size of DM sib population ( 1 . 54 DM offspring per DM parent , in 968 DM parents ) . |
[
{
"name": "DM",
"pos": [
152,
154
],
"type": "Disease"
}
] | We conclude that ( 1 ) intergenerational contractions of the CTG repeat in leukocyte DNA frequently accompanies apparent anticipation , especially when DM is maternally transmitted , and ( 2 ) the paternal origin of the repeat and the presence of the repeat contraction in a sibling increase the probability of the CTG repeat contraction |
[
{
"name": "myotonic dystrophy",
"pos": [
23,
41
],
"type": "Disease"
}
] | Gonosomal mosaicism in myotonic dystrophy patients : involvement of mitotic events in ( CTG ) n repeat variation and selection against extreme expansion in sperm . |
[
{
"name": "Myotonic dystrophy",
"pos": [
0,
18
],
"type": "Disease"
},
{
"name": "DM",
"pos": [
21,
23
],
"type": "Disease"
},
{
"name": "DM",
"pos": [
109,
111
],
"type": "Disease"
}
] | Myotonic dystrophy ( DM ) is caused by abnormal expansion of a polymorphic ( CTG ) n repeat , located in the DM protein kinase gene . |
[
{
"name": "DM",
"pos": [
144,
146
],
"type": "Disease"
}
] | We determined the ( CTG ) n repeat lengths in a broad range of tissue DNAs from patients with mild , classical , or congenital manifestation of DM . |
[
{
"name": "DM",
"pos": [
74,
76
],
"type": "Disease"
}
] | Differences in the repeat length were seen in somatic tissues from single DM individuals and twins . |
[] | Repeats appeared to expand to a similar extent in tissues originating from the same embryonal origin . |
[] | In most male patients carrying intermediate - or small - sized expansions in blood , the repeat lengths covered a markedly wider range in sperm . |
[] | In contrast , male patients with large allele expansions in blood ( > 700 CTGs ) had similar or smaller repeats in sperm , when detectable . |
[] | Sperm alleles with > 1 , 000 CTGs were not seen . |
[
{
"name": "DM",
"pos": [
17,
19
],
"type": "Disease"
}
] | We conclude that DM patients can be considered gonosomal mosaics , i . |
[] | e e . , combined somatic and germ - line tissue mosaics . |
[] | Most remarkably , we observed multiple cases where the length distributions of intermediate - or small - sized alleles in fathers sperm were significantly different from that in their offsprings blood . |
[] | Our combined findings indicate that intergenerational length changes in the unstable CTG repeat are most likely to occur during early embryonic mitotic divisions in both somatic and germ - line tissue formation . |
[] | Both the initial CTG length , the overall number of cell divisions involved in tissue formation , and perhaps a specific selection process in spermatogenesis may influence the dynamics of this process . |
[
{
"name": "DM",
"pos": [
84,
86
],
"type": "Disease"
}
] | A model explaining mitotic instability and sex - dependent segregation phenomena in DM manifestation is discussed |
[
{
"name": "APC",
"pos": [
21,
24
],
"type": "Disease"
},
{
"name": "adenomatous polyposis coli",
"pos": [
129,
155
],
"type": "Disease"
}
] | Regionally clustered APC mutations are associated with a severe phenotype and occur at a high frequency in new mutation cases of adenomatous polyposis coli . |
[
{
"name": "adenomatous polyposis coli",
"pos": [
83,
109
],
"type": "Disease"
},
{
"name": "APC",
"pos": [
112,
115
],
"type": "Disease"
}
] | Germline mutation in APC at 5q21 - 22 results in the dominantly inherited syndrome adenomatous polyposis coli ( APC ) . |
[] | Somatic mutation in this gene is an early event in colorectal tumourigenesis . |
[] | Both types of mutation are concentrated in the 5 half of exon 15 . |
[] | We have used single strand conformational polymorphism ( SSCP ) and heteroduplex analysis to screen for variants in this region of the gene in a total of 45 affected but unrelated individuals . |
[
{
"name": "cancer",
"pos": [
157,
163
],
"type": "Disease"
}
] | Eighteen patients had no family history of the disease ; of these 11 were classified as having a severe phenotype , based on an early age at presentation or cancer development . |
[] | This compared with 6 of 27 familial cases . |
[
{
"name": "APC",
"pos": [
75,
78
],
"type": "Disease"
}
] | A 5 bp deletion at codon 1309 reported to occur in 10 - 15 % of unselected APC patients worldwide , was found in 5 of the 18 new mutation cases and 4 of the 27 familial cases all nine were classed as severe . |
[] | A further 3 new mutations and 1 familial mutation were located downstream from codon 1309 , these individuals similarly being classed as phenotypically severe . |
[
{
"name": "APC",
"pos": [
23,
26
],
"type": "Disease"
}
] | In contrast all of the APC mutations detected in affected individuals with an average phenotype were located prior to codon 1309 . |
[] | The frequent association of a severe phenotype with fresh mutation may explain the apparent conflict of a high mutation rate ( 20 - 30 % ) in a condition , which on average , is lethal at a post - reproductive age . . |
[
{
"name": "anterior segment malformations",
"pos": [
55,
85
],
"type": "Disease"
},
{
"name": "Peters ' anomaly",
"pos": [
96,
112
],
"type": "Disease"
}
] | Mutations at the PAX6 locus are found in heterogeneous anterior segment malformations including Peters ' anomaly . |
[
{
"name": "aniridia",
"pos": [
62,
70
],
"type": "Disease"
}
] | Mutation or deletion of the PAX6 gene underlies many cases of aniridia . |
[
{
"name": "anterior segment malformations",
"pos": [
70,
100
],
"type": "Disease"
},
{
"name": "Peters anomaly",
"pos": [
111,
125
],
"type": "Disease"
}
] | Three lines of evidence now converge to implicate PAX6 more widely in anterior segment malformations including Peters anomaly . |
[
{
"name": "Peters anomaly",
"pos": [
21,
35
],
"type": "Disease"
}
] | First , a child with Peters anomaly is deleted for one copy of PAX6 . |
[
{
"name": "anterior segment malformations",
"pos": [
64,
94
],
"type": "Disease"
},
{
"name": "Peters anomaly",
"pos": [
107,
121
],
"type": "Disease"
}
] | Second , affected members of a family with dominantly inherited anterior segment malformations , including Peters anomaly are heterozygous for an R26G mutation in the PAX6 paired box . |
[
{
"name": "Peters anomaly",
"pos": [
141,
155
],
"type": "Disease"
}
] | Third , a proportion of Sey / + Smalleye mice , heterozygous for a nonsense mutation in murine Pax - 6 , have an ocular phenotype resembling Peters anomaly . |
[
{
"name": "anterior segment anomalies",
"pos": [
39,
65
],
"type": "Disease"
}
] | We therefore propose that a variety of anterior segment anomalies may be associated with PAX6 mutations . . |
[
{
"name": "Huntington disease",
"pos": [
0,
18
],
"type": "Disease"
}
] | Huntington disease without CAG expansion : phenocopies or errors in assignment ? |
[
{
"name": "Huntington disease",
"pos": [
0,
18
],
"type": "Disease"
},
{
"name": "HD",
"pos": [
21,
23
],
"type": "Disease"
}
] | Huntington disease ( HD ) has been shown to be associated with an expanded CAG repeat within a novel gene on 4p16 . |
[] | 3 ( IT15 ) . |
[] | A total of 30 of 1 , 022 affected persons ( 2 . 9 % of our cohort ) did not have an expanded CAG in the disease range . |
[
{
"name": "HD",
"pos": [
303,
305
],
"type": "Disease"
}
] | The reasons for not observing expansion in affected individuals are important for determining the sensitivity of using repeat length both for diagnosis of affected patients and for predictive testing programs and may have biological relevance for the understanding of the molecular mechanism underlying HD . |
[] | Here we show that the majority ( 18 ) of the individuals with normal sized alleles represent misdiagnosis , sample mix - up , or clerical error . |
[
{
"name": "HD",
"pos": [
61,
63
],
"type": "Disease"
}
] | The remaining 12 patients represent possible phenocopies for HD . |
[] | In at least four cases , family studies of these phenocopies excluded 4p16 . |
[] | 3 as the region responsible for the phenotype . |
[
{
"name": "HD",
"pos": [
17,
19
],
"type": "Disease"
},
{
"name": "HD",
"pos": [
263,
265
],
"type": "Disease"
}
] | Mutations in the HD gene that are other than CAG expansion have not been excluded for the remaining eight cases ; however , in as many as seven of these persons , retrospective review of these patients clinical features identified characteristics not typical for HD . |
[] | This study shows that on rare occasions mutations in other , as - yet - undefined genes can present with a clinical phenotype very similar to that of HD |
[
{
"name": "advanced prostate cancers",
"pos": [
74,
99
],
"type": "Disease"
}
] | Frequent detection of codon 877 mutation in the androgen receptor gene in advanced prostate cancers . |
[
{
"name": "metastatic prostate cancer",
"pos": [
82,
108
],
"type": "Disease"
}
] | Prostatic tissue specimens derived from transurethral resections of patients with metastatic prostate cancer were analyzed for genetic alterations in the hormone - binding domain of the androgen receptor ( AR ) gene . |
[] | Direct sequencing of the polymerase chain reaction - derived DNAs of 6 of 24 specimens revealed a codon 877 mutation ( ACT - - > GCT , Thr - - > Ala ) in the hormone - binding domain of the AR gene . |
[
{
"name": "metastatic prostate cancer",
"pos": [
56,
82
],
"type": "Disease"
}
] | This same AR mutation has been reported previously in a metastatic prostate cancer cell line , LNCaP , where this mutation confers upon the AR an altered ligand - binding specificity which is stimulated by estrogens , progestagens , and antiandrogens . |
[
{
"name": "advanced prostate cancer",
"pos": [
209,
233
],
"type": "Disease"
}
] | It is possible that analogous to an activated / altered growth factor receptor oncogene , codon 877 mutant AR with altered ligand binding may provide a selective growth advantage in the genesis of a subset of advanced prostate cancer . |
[
{
"name": "advanced prostate cancer",
"pos": [
117,
141
],
"type": "Disease"
}
] | Although estrogens are used infrequently , antiandrogens are used increasingly in hormonal therapy for patients with advanced prostate cancer . |
[] | The stimulatory effect of these therapeutic agents on the codon 877 mutant AR further suggests that this frequently observed AR mutation may contribute to the treatment refractory disease . . |
[
{
"name": "alkaptonuria",
"pos": [
19,
31
],
"type": "Disease"
},
{
"name": "AKU",
"pos": [
34,
37
],
"type": "Disease"
}
] | The human gene for alkaptonuria ( AKU ) maps to chromosome 3q . |
[
{
"name": "Alkaptonuria",
"pos": [
0,
12
],
"type": "Disease"
},
{
"name": "AKU",
"pos": [
15,
18
],
"type": "Disease"
},
{
"name": "autosomal recessive disorder",
"pos": [
54,
82
],
"type": "Disease"
}
] | Alkaptonuria ( AKU ; McKusick no . 203500 ) is a rare autosomal recessive disorder caused by the lack of homogentisic acid oxidase activity . |
[] | Patients excrete large amounts of homogentisic acid in their urine and a black ochronotic pigment is deposited in their cartilage and collagenous tissues . |
[
{
"name": "Ochronosis",
"pos": [
0,
10
],
"type": "Disease"
},
{
"name": "ochronotic arthropathy",
"pos": [
78,
100
],
"type": "Disease"
}
] | Ochronosis is the predominant clinical complication of the disease leading to ochronotic arthropathy , dark urine , pigment changes of the skin , and other clinical features . |
[
{
"name": "alkaptonuria",
"pos": [
19,
31
],
"type": "Disease"
}
] | A mutation causing alkaptonuria in the mouse has mapped to chromosome 16 . |
[
{
"name": "alkaptonuria",
"pos": [
91,
103
],
"type": "Disease"
}
] | Considering conserved synteny , we were able to map the human gene to chromosome 3q in six alkaptonuria pedigrees of Slovak origin . . |
[] | Structure of the human Na + / glucose cotransporter gene SGLT1 . |
[] | Intestinal uptake of dietary glucose and galactose is mediated by the SGLT1 Na + / glucose cotransporter of the brush border . |
[
{
"name": "hereditary glucose / galactose malabsorption",
"pos": [
37,
81
],
"type": "Disease"
},
{
"name": "diarrhea",
"pos": [
119,
127
],
"type": "Disease"
},
{
"name": "diarrhea",
"pos": [
226,
234
],
"type": "Disease"
}
] | An SGLT1 missense mutation underlies hereditary glucose / galactose malabsorption , characterized by potentially fatal diarrhea ; conversely , oral rehydration therapy exploits normal transport to alleviate life - threatening diarrhea of infectious origin . |
[] | We have mapped the entire human SGLT1 Na + / glucose cotransporter gene from cosmid and lambda phage clones representing a genomic region of 112 kilobases . |
[] | Transcription initiation occurred from a site 27 base pairs 3 of a TATAA sequence . |
[] | All exon - flanking regions were sequenced , and the entire 112 - kilobase region mapped with four restriction enzymes . |
[] | SGLT1 is comprised of 15 exons ( spanning 72 kilobases ) ; a possible evolutionary origin from a six - membrane - span ancestral precursor via a gene duplication event is suggested from comparison of exons against protein secondary structure and from sequence considerations . |
[
{
"name": "glucose / galactose malabsorption",
"pos": [
42,
75
],
"type": "Disease"
}
] | A new missense mutation in exon 1 causing glucose / galactose malabsorption is also described . |
[] | This is the first Na ( + ) - dependent cotransporter gene structure reported . |
[
{
"name": "glucose / galactose malabsorption",
"pos": [
41,
74
],
"type": "Disease"
}
] | These data facilitate the search for new glucose / galactose malabsorption - related mutations in this important gene and provide a basis for future evolutionary comparisons with other Na ( + ) - dependent cotransporters . . |
[
{
"name": "prolidase deficiency",
"pos": [
32,
52
],
"type": "Disease"
}
] | Four novel PEPD alleles causing prolidase deficiency . |
[
{
"name": "prolidase deficiency",
"pos": [
34,
54
],
"type": "Disease"
},
{
"name": "autosomal recessive disorder",
"pos": [
84,
112
],
"type": "Disease"
},
{
"name": "iminodipeptiduria",
"pos": [
130,
147
],
"type": "Disease"
},
{
"name": "skin ulcers",
"pos": [
150,
161
],
"type": "Disease"
},
{
"name": "mental retardation",
"pos": [
164,
182
],
"type": "Disease"
}
] | Mutations at the PEPD locus cause prolidase deficiency ( McKusick 170100 ) , a rare autosomal recessive disorder characterized by iminodipeptiduria , skin ulcers , mental retardation , and recurrent infections . |
[] | Four PEPD mutations from five severely affected individuals were characterized by analysis of reverse - transcribed , PCR - amplified ( RT - PCR ) cDNA . |
[] | We used SSCP analysis on four overlapping cDNA fragments covering the entire coding region of the PEPD gene and detected abnormal SSCP bands for the fragment spanning all or part of exons 13 - 15 in three of the probands . |
[] | Direct sequencing of the mutant cDNAs showed a G - - > A , 1342 substitution ( G448R ) in two patients and a 3 - bp deletion ( delta E452 or delta E453 ) in another . |
[] | In the other two probands the amplified products were of reduced size . |
[] | Direct sequencing of these mutant cDNAs revealed a deletion of exon 5 in one patient and of exon 7 in the other . |
[] | Intronic sequences flanking exons 5 and 7 were identified using inverse PCR followed by direct sequencing . |