A domain mutations in 65 haemophilia A families and molecular modelling of dysfunctional factor VIII proteins

Liu, Miao‐Liang; Murphy, M.E.P.; Thompson, Arthur R.

doi:10.1046/j.1365-2141.1998.01122.x

Cited by 39 publications

(45 citation statements)

References 33 publications

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“…Subsequent sequencing of the F8 gene revealed hemizygosity for the point mutation c.6089G>A (p.S2030N), which has been associated with mild haemophilia A (http://hadb.org.uk/). 35 The identification of this mutation explains the patient's mild haemophilic phenotype. An additional investigation included a karyotype, fragile X DNA testing, CPK level assay and thyroid function tests, all of which were normal.…”

Section: Resultsmentioning

confidence: 99%

Int22h-1/int22h-2-mediated Xq28 rearrangements: intellectual disability associated with duplications and in utero male lethality with deletions

El‐Hattab

Fang

Jin

et al. 2011

Journal of Medical Genetics

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Background X linked intellectual disability (XLID) is common, with an estimated prevalence of 1/1000. The expanded use of array comparative genomic hybridisation (CGH) has led to the identification of several XLID-associated copy-number variants. Methods Array CGH analysis was performed using chromosomal microarray with w105 000 oligonucleotides covering the entire genome. Confirmatory fluorescence in situ hybridisation analyses were subsequently performed. Chromosome X-inactivation (XCI) was assessed using methylation-sensitive restriction enzyme digestion followed by PCR amplification. Results A novel w0.5 Mb duplication in Xq28 was identified in four cognitively impaired males who share behavioural abnormalities (hyperactivity and aggressiveness) and characteristic facial features (high forehead, upper eyelid fullness, broad nasal bridge and thick lower lip). These duplications were inherited from mothers with skewed XCI and are mediated by nonallelic homologous recombination between the low-copy repeat regions int22h-1 and int22h-2, which, in addition to int22h-3, are also responsible for inversions disrupting the factor VIII gene in haemophilia A. In addition, we have identified a reciprocal deletion in a girl and her mother, both of whom exhibit normal cognition and completely skewed XCI. The mother also had two spontaneous abortions. Conclusions The phenotypic similarities among subjects with int22h-1/int22h-2-mediated Xq28 duplications suggest that such duplications are responsible for a novel XLID syndrome. The reciprocal deletion may not be associated with a clinical phenotype in carrier females due to skewed XCI, but may be lethal for males in utero. Advancements in array CGH technology have enabled the identification of such small, clinically relevant copy-number variants.

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Section: Resultsmentioning

confidence: 99%

Int22h-1/int22h-2-mediated Xq28 rearrangements: intellectual disability associated with duplications and in utero male lethality with deletions

El‐Hattab

Fang

Jin

et al. 2011

Journal of Medical Genetics

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“…Small deletions in B domain have been observed to give rise to milder forms of HA [19]. The residue Asn1460 is reported to be hypermutable with both insertion i.e.…”

Section: Discussionmentioning

confidence: 99%

Mutations in Intron 1 and Intron 22 Inversion Negative Haemophilia A Patients from Western India

et al. 2014

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Despite increased awareness and diagnostic facilities, 70–80% of the haemophilia A (HA) patients still remain undiagnosed in India. Very little data is available on prevalent mutations in HA from this country. We report fifty mutations in seventy one Indian HA patients, of which twenty were novel. Ten novel missense mutations [p.Leu11Pro (p.Leu-8Pro), p.Tyr155Ser (p.Tyr136Ser), p.Ile405Thr (p.Ile386Thr), p.Gly582Val (p.Gly563Val) p.Thr696Ile (p.Thr677Ile), p.Tyr737Cys (p.Tyr718Cys), p.Pro1999Arg (p.Pro1980Arg), p.Ser2082Thr (p.Ser2063Thr), p.Leu2197Trp (p.Leu2178Trp), p.Asp2317Glu (p.Asp2298Glu)] two nonsense [p.Lys396* (p.Lys377*), p.Ser2205* (p.Ser2186*)], one insertion [p.Glu1268_Asp1269ins (p.Glu1249_Asp1250)] and seven deletions [p.Leu882del (p.Leu863del), p.Met701del (p.Met682del), p.Leu1223del (p.Leu1204del), p.Trp1961_Tyr1962del (p.Trp1942_Tyr1943del) p.Glu1988del (p.Glu1969del), p.His1841del (p.His1822del), p.Ser2205del (p.Ser2186del)] were identified. Double mutations (p.Asp2317Glu; p.Thr696Ile) were observed in a moderate HA case. Mutations [p. Arg612Cys (p.Arg593Cys), p.Arg2326Gln (p.Arg2307Gln)] known to be predisposing to inhibitors to factor VIII (FVIII) were identified in two patients. 4.6% of the cases were found to be cross reacting material positive (CRM+ve). A wide heterogeneity in the nature of mutations was seen in the present study which has been successfully used for carrier detection and antenatal diagnosis in 10 families affected with severe to moderate HA.

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“…Another possible mutation hot-spot could be the 7A-stretch in exon 18, codons 1967-1968, since deletions or insertion of A at this position have been described in couple of unrelated patients [Becker et al, 1996;Pieneman et al, 1995;Liu et al, 1998;present study]. From crystal structures and studies in solution, it is generally known for A-tracts in DNA that they develop distinctive B' structure, essentially straight and more rigid than the generic Bform DNA (McConnell and Beveridge, 2001;MacDonald et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Prevalence of small rearrangements in the factor VIII gene F8C among patients with severe hemophilia A

Bogdanova

Markoff²,

Pollmann

et al. 2002

Hum. Mutat.

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Hemophilia A is a common X-linked bleeding disorder caused by various types of mutations in the factor VIII gene F8C. The most common intron 22-inversion is responsible for about 40% of the severe hemophilia A cases while large deletions, point mutations and small (less than 100 bp) deletions or insertions are responsible for the disease in the rest of patients. We report on nine novel (6 deletions, two indels and one partial duplication) and five recurrent small rearrangements identified in 15 German patients with severe hemophilia A, negative for the intron 22-inversion. c.2208-2214delTTATTAC/c.2207-2215insCTCTT and c.4665-4678del/c.4664-4678insAAGGAA identified in the present study are the first small indels described in the factor VIII gene. Our analyses suggest that the prevalence of this type of mutations (predominantly located in exon 14) among patients with severe phenotype and negative for the common intron 22-inversion, is about 30%. The correlation between these molecular defects and formation of factor VIII inhibitors as well as the parental origin of the de novo mutations are evaluated. Finally we show that denaturing HPLC (DHPLC) and classic heteroduplex analysis (HA) are able to detect these sequence alterations on 100% and could be preferred as a screening approach when analysing for mutations in factor VIII in severely affected patients.

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A domain mutations in 65 haemophilia A families and molecular modelling of dysfunctional factor VIII proteins

Cited by 39 publications

References 33 publications

Int22h-1/int22h-2-mediated Xq28 rearrangements: intellectual disability associated with duplications and in utero male lethality with deletions

Int22h-1/int22h-2-mediated Xq28 rearrangements: intellectual disability associated with duplications and in utero male lethality with deletions

Mutations in Intron 1 and Intron 22 Inversion Negative Haemophilia A Patients from Western India

Prevalence of small rearrangements in the factor VIII gene F8C among patients with severe hemophilia A

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