RECURRENT MUTATIONS AND AN UNUSUAL DELETION IN HEMOPHILIA A

1987 ◽  
Author(s):  
H Youssoufiän ◽  
A Patel ◽  
D Phillips ◽  
H H Kazazian ◽  
S E Antonarakis
Keyword(s):  
Hemophilia A ◽  
De Novo ◽  
Donor Site ◽  
Point Mutations ◽  
Paternal Age ◽  
De Novo Mutations ◽  
Recurrent Point ◽  
Deletion Event ◽  
Recurrent Mutations ◽  
Oligonucleotide Hybridization

We have identified 15 mutations of the factor VIII (F8) gene from a panel of 107 patients with hemophilia A and have characterized these gene defects byrestriction analysis, oligonucleotide hybridization, cloning and DNA sequencing. Recurrent point mutations that involve CG to TG transitions were identified in exon 18, exon 22, and exon 24; a single CG to TG transition was identified in exon 23; and a CG to CA transition was identified in exon 24. In addition, a Taq I site alteration in intron 4 was identified in a patient with mild hemophilia, which arose dg. S23&in a grandpaternal germ cell. Cloning and sequencing of this region suggests the generation of a newsplice donor site. These data suggest that CG to TG transition is a prominent mechanism of mutation in hemophilia A. Six different deletions were also characterized. In one family, the deletion involved exon 26. However, the deletion endpoints in the male proband were different from those in his carrier mother, suggesting either gonadal mosaicism or a second deletion event in maternal meiosis.Of the 15 mutations, 6 occurred de novo within 2 generations: 4 in males and 2 in females. In these djg.novo mutations paternal age at conception was 35 (range = 32-38) and maternal age was 24 and 27. The ability to discover a sizable number of mutations in the F8 gene producing hemophilia A enables us to determine the frequency and nature of de novo mutations in man.

Schizophrenia Risk and Paternal Age: A Potential Role for De Novo Mutations in Schizophrenia Vulnerability Genes

CNS Spectrums ◽  
2002 ◽  
Vol 7 (1) ◽  
pp. 26-29 ◽  
Author(s):  
Dolores Malaspina ◽  
Alan Brown ◽  
Deborah Goetz ◽  
Nelly Alia-Klein ◽  
Jill Harkavy-Friedman ◽  
...  
Keyword(s):  
Human Population ◽  
Potential Role ◽  
De Novo ◽  
Paternal Age ◽  
Current Evidence ◽  
Parental Age ◽  
De Novo Mutations ◽  
New Mutations

ABSTRACTHow schizophrenia (SZ) is maintained at roughly 1% of the population despite diminished reproduction is one puzzle currently facing researchers. De novo mutations were first proposed over half a century ago as a source for new SZ genes. Current evidence linking advancing paternal age to SZ risk makes revisiting this hypothesis important. Advancing paternal age is the major source of new mutations in the human population. This article will examine potential mechanisms whereby parental age may impact new mutations, as well as review recent data supporting such a hypothesis.

The Molecular Genetics of Hemophilia A Stylianos

1987 ◽  
Author(s):  
E Antonarakis
Keyword(s):  
Amino Acids ◽  
Dna Sequences ◽  
Hemophilia A ◽  
Restriction Analysis ◽  
Point Mutations ◽  
Leader Peptide ◽  
Molecular Defect ◽  
Severe Hemophilia ◽  
Cpg Dinucleotides ◽  
Oligonucleotide Hybridization

Hemophilia A is a common X linked hereditary disorder of blood coagulation due to deficiency of factor 8. The gene for factor 8 has been cloned and characterized (Nature 312:326-342, 1984). It is divided into 26 exons and 25 introns and spans 186 kb of DNA. The CGNA is 9 kb and codes for 2351 amino acids. The first 19 amino acids comprise the secretory leader peptide and the mature excreted polypeptide consists of 2332 amino acids. The nucleotide sequence of the exons and the exon-intron junctions is known and the complete amino acid sequence has been deducedSeveral laboratories have used cloned factor 8 DNA sequences as probes to characterized mutations that are responsible for hemophilia A in certain pedigrees. These mutations have been characterized by restriction analysis, oligonucleotide hybridization, cloning and sequencing of DNA from appropriate patientsIn about 500 patients with hemophilia A examined, the molecular defect has been recognized in 39. Both gross alterations (mainly deletions) and point mutations of the factor 8 gene have been found.A total of 19 different deletions have been observed. No two unrelated pedigrees share the same exact deletion.The size of the deleted DNA varies from 1.5 kb to more than 210 kb. All but one of these deletions are associated with severe hemophilia A. A deletion of 6 kb that contains exon 22 only is associated with moderate hemophilia. Some deletions are present in patients with inhibitors to factor 8. No correlation of the size or the position of the deletions can be found with the presence of inhibitors to factor 8.A total of 20 point mutations have been characterized. All are recognized by restriction analysis and involve Taq I sites. All are mutations of CpG dinucleotides and generate nonsense or missence codons. Unrelated pedigrees have the same single nucleotide change because of independent origin of the same mutation. In many instances de novo occurrence of a point mutation has been observed. CpG dinucleotides are hot spots for mutation to TG or CA presumably because of spontaneous deamination of methylcytosine. Some point mutations are present in patients with inhibitors but no correlation of the site of mutation and inhibitor formation has been found. The nonsense mutations are present in patients with severe hemophilia A. A missense mutation (Arg Gin) in exon 26 was found in a patient with mild hemophilia while another Arg Gin mutation in exon 24 has been observed in a patient with severe disease. The creation of a donor splice site in IVS 4 of factor 8 gene has been observed in a patient with mild hemophilia.Few DNA polymorphisms within the factor 8 gene and two other closely linked polymorphisms have been used for carrier detection and prenatal diagnosis of hemophilia A. These DNA markers are useful in more than 90% of families at risk for hemophilia A.The author thanks Drs. Gitschier, Din, Olek, Pirastou, Lawn for communication of their data prior to publication.The hemophilia project at Johns Hopkins was supported by an Institutional grant and NIH grant to S.S.A. and Haig H. Kazazian, Jr.

RUNX1 DNA-Binding Mutations and RUNX1-PRDM16 Cryptic Fusion in BCR/ABL+ Leukemias Are Frequently Associated with Secondary Trisomy 21 and May Contribute to Clonal Evolution and Imatinib Resistance.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2786-2786
Author(s):  
Catherine Roche-Lestienne ◽  
Laureline Deluche ◽  
Selim Corm ◽  
Isabelle Tigaud ◽  
Sami Joha ◽  
...  
Keyword(s):  
Dna Binding ◽  
Disease Progression ◽  
High Frequency ◽  
Trisomy 21 ◽  
De Novo ◽  
Point Mutations ◽  
Imatinib Resistance ◽  
Exon 2 ◽  
Molecular Abnormalities ◽  
Recurrent Mutations

Abstract Background: Besides the extensively studied point mutations in the BCR/ABL TK domain as the clinically most important cause of imatinib (IM) resistance either in CML and Philadelphia-positive (Ph+) ALL, additional acquired genetic events contributing to resistance/disease progression are not fully understood. Many evidences suggest that the enhanced survival and differentiation arrest of the CML blast crisis (BC) cells depends on the cooperation of BCR/ABL with other genes deregulated during disease progression. A recent study has identified RUNX1/AML1 transcription factor gene as a modulator of the cellular response towards IM in vitro and in vivo in mice, suggesting its possible involvement in disease persistence in IM-resistant CML patients. Purpose: We investigated RUNX1 molecular abnormalities (point mutations or cryptic chromosomal RUNX1 translocation to a novel recently described gene partner PRDM16 at 1p36) in 18 Ph+ leukemias. The observation that RUNX1 mutated allele is frequently duplicated by acquired trisomy of the altered chromosome 21 in acute myeloblastic leukemias (AML) prompt us to focus our analysis on a selected cohort (1 CP-CML, 3 AP-CML, 8 myeloid BC, 1 lymphoid BC, 2 de novo Ph+ ALL-B, 1 de novo AML and 1 therapy-related- Ph+ ALL) presenting acquired trisomy 21 along disease course. Methods: From peripheral blood leucocytes, recurrent mutations were investigated by sequencing DNA PCR fragments corresponding to exon 3 to 8 of RUNX1. RUNX1-PRDM16 fusion was investigated by RT-PCR (i.e. RUNX1 exon 5-PRDM16 exon 2 junction) and by FISH using the TEL/AML1 dual color/dual fusion translocation probes (Vysis, Downer’s grove, IL, USA). Results: We report a high frequency (33%) of recurrent point mutations (4 in myeloid BC CML and 1 in CP-CML) within the DNA-binding region of RUNX1. We did not find any mutation in de novo BCR/ABL+ ALLs or lymphoid BC CMLs. Onset of RUNX1 mutations was detected at diagnosis or before the acquisition of trisomy 21. We also report a high frequency of RUNX1-PRDM16 fusion for 3 out of 7 investigated patients: 2 CMLs and, for the first time reported to our knowledge, 1 therapy-related BCR/ABL+ ALL. RUNX1-PRDM16 is probably transcribed at low levels since only few bone marrow metaphases with trisomy 21 were t(1;21)(p36;q22) positive. Two patients presented both RUNX1 mutations and RUNX1-PRDM16 fusion. All these events are associated with a poor survival: 14 out of 18 patients died with a median survival of 3 months after the diagnosis of the acquired clonal trisomy 21. Furthermore, none of the patients in our study raised durable optimal responses to IM. Conclusion: Our data support the concept of a cooperative effect of BCR/ABL with molecular RUNX1 abnormalities on the differentiation arrest phenotype observed during progression of CML and in BCR/ABL+ ALL. Our findings also support that it may exist a heterogeneous genetic status at diagnosis of CML, underlying the need of further investigations able to define more precisely the molecular disease characteristics at diagnosis for better therapeutic decision adjustments.

scholarly journals Advancing paternal age and offspring violent offending: A sibling-comparison study

2012 ◽  
Vol 24 (3) ◽  
pp. 739-753 ◽  
Author(s):  
Ralf Kuja-Halkola ◽  
Yudi Pawitan ◽  
Brian M. D'Onofrio ◽  
Niklas Långström ◽  
Paul Lichtenstein
Keyword(s):  
Violent Crime ◽  
De Novo ◽  
Causal Effect ◽  
Paternal Age ◽  
De Novo Mutations ◽  
Criminal Convictions ◽  
Violent Offending ◽  
Genes And Environment ◽  
Life Course Persistent ◽  
Severe Psychopathology

AbstractChildren born to older fathers are at higher risk to develop severe psychopathology (e.g., schizophrenia and bipolar disorder), possibly because of increased de novo mutations during spermatogenesis with older paternal age. Because severe psychopathology is correlated with antisocial behavior, we examined possible associations between advancing paternal age and offspring violent offending. Interlinked Swedish national registers provided information on fathers' age at childbirth and violent criminal convictions in all offspring born from 1958 to 1979 (N= 2,359,921). We used ever committing a violent crime and number of violent crimes as indices of violent offending. The data included information on multiple levels; we compared differentially exposed siblings in within-family analyses to rigorously test causal influences. In the entire population, advancing paternal age predicted offspring violent crime according to both indices. Congruent with a causal effect, this association remained for rates of violent crime in within-family analyses. However, in within-family analyses, we found no association with ever committing a violent crime, suggesting that factors shared by siblings (genes and environment) confounded this association. Life-course persistent criminality has been proposed to have a partly biological etiology; our results agree with a stronger biological effect (i.e., de novo mutations) on persistent violent offending.

Risk of Psychiatric Illness From Advanced Paternal Age Is Not Predominantly From De Novo Mutations

2017 ◽  
Vol 72 (2) ◽  
pp. 96
Author(s):  
Jacob Gratten ◽  
Naomi R. Wray ◽  
Wouter J. Peyrot ◽  
John J. McGrath ◽  
Peter M. Visscher ◽  
...  
Keyword(s):  
Psychiatric Illness ◽  
De Novo ◽  
Paternal Age ◽  
De Novo Mutations ◽  
Advanced Paternal Age

scholarly journals Impact of Paternal Age at Conception on Human Health

2019 ◽  
Vol 65 (1) ◽  
pp. 146-152 ◽  
Author(s):  
Mathieu Simard ◽  
Catherine Laprise ◽  
Simon L Girard
Keyword(s):  
Maternal Age ◽  
De Novo ◽  
Autism Spectrum ◽  
Age Effect ◽  
Age Effects ◽  
Paternal Age ◽  
De Novo Mutations ◽  
Brain Functions ◽  
Offspring Health ◽  
Paternal Age Effect

Abstract BACKGROUND The effect of maternal age at conception on various aspects of offspring health is well documented and often discussed. We seldom hear about the paternal age effect on offspring health, although the link is now almost as solid as with maternal age. The causes behind this, however, are drastically different between males and females. CONTENT In this review article, we will first examine documented physiological changes linked to paternal age effect. We will start with all morphological aspects of the testis that have been shown to be altered with aging. We will then move on to all the parameters of spermatogenesis that are linked with paternal age at conception. The biggest part of this review will focus on genetic changes associated with paternal age effects. Several studies that have established a strong link between paternal age at conception and the rate of de novo mutations will be reviewed. We will next discuss paternal age effects associated with telomere length and try to better understand the seemingly contradictory results. Finally, severe diseases that affect brain functions and normal development have been associated with older paternal age at conception. In this context, we will discuss the cases of autism spectrum disorder and schizophrenia, as well as several childhood cancers. SUMMARY In many Western civilizations, the age at which parents have their first child has increased substantially in recent decades. It is important to summarize major health issues associated with an increased paternal age at conception to better model public health systems.

scholarly journals Paternal age and sporadic schizophrenia: Evidence for de novo mutations

2002 ◽  
Vol 114 (3) ◽  
pp. 299-303 ◽  
Author(s):  
Dolores Malaspina ◽  
Cheryl Corcoran ◽  
Cherine Fahim ◽  
Ariela Berman ◽  
Jill Harkavy-Friedman ◽  
...  
Keyword(s):  
De Novo ◽  
Paternal Age ◽  
De Novo Mutations

scholarly journals Identification of intron 1 and intron 22 inversions of factor VIII gene in Serbian patients with hemophilia A

Genetika ◽  
2013 ◽  
Vol 45 (1) ◽  
pp. 207-216 ◽  
Author(s):  
Nina Ilic ◽  
Aleksandra Krstic ◽  
Milos Kuzmanovic ◽  
Dragan Micic ◽  
Nada Konstantinidis ◽  
...  
Keyword(s):  
Health Care ◽  
Hemophilia A ◽  
De Novo ◽  
Family Members ◽  
Carrier Status ◽  
Type I ◽  
Intron 1 ◽  
Mother And Child Health ◽  
Recurrent Mutations ◽  
Mother And Child

Hemophilia A (HA) is a common X-linked recessive bleeding disease caused by mutations of FVIII gene. Inversion of intron 1 (inv1) and intron 22 (inv22) are recurrent mutations in severe HA, causing 50% of cases. Inv1 has been reported to occur in 2-5% and inv 22 in 45% of severe HA patients. Our objective was to determine, for the first time in Serbia, the frequency of inv1 and inv22 in a group of severe HA patients and to compare these data with those from other countries. Study subjects were 50 HA patients, diagnosed and treated from April 2009 to June 2012 at Mother and Child Health Care Institute of Serbia ?Dr Vukan Cupic? (IHS) and Institute for Child and Youth Health Care of Vojvodina (IHV).The presence of inv1 and inv22 was analyzed using Inverse shifting PCR (IS-PCR). Our results revealed that the frequencies of inv1 and inv22 in the cohort of Serbian patients were 6 % and 42% (34% of inv22 type I and 8% of inv22 type II) respectively . These frequencies were in line with those found in other populations. Carrier status analyses of 65 family members (mothers and sisters) showed the de novo inversion of intron 22 in one patient. Genetic Counseling Units of IHS and IHV provide the adequate genetic advice to all HA affected patients and their family members.

Risk of psychiatric illness from advanced paternal age is not predominantly from de novo mutations

2016 ◽  
Vol 48 (7) ◽  
pp. 718-724 ◽  
Author(s):  
Jacob Gratten ◽  
Naomi R Wray ◽  
Wouter J Peyrot ◽  
John J McGrath ◽  
Peter M Visscher ◽  
...  
Keyword(s):  
Psychiatric Illness ◽  
De Novo ◽  
Paternal Age ◽  
De Novo Mutations ◽  
Advanced Paternal Age

scholarly journals Older fathers' children have lower evolutionary fitness across four centuries and in four populations

2017 ◽  
Vol 284 (1862) ◽  
pp. 20171562 ◽  
Author(s):  
Ruben C. Arslan ◽  
Kai P. Willführ ◽  
Emma M. Frans ◽  
Karin J. H. Verweij ◽  
Paul-Christian Bürkner ◽  
...  
Keyword(s):  
Reproductive Success ◽  
De Novo ◽  
Age Effects ◽  
Paternal Age ◽  
De Novo Mutations ◽  
Negative Effects ◽  
Older Parents ◽  
Plausible Model ◽  
Large Populations ◽  
Sibling Control

Higher paternal age at offspring conception increases de novo genetic mutations. Based on evolutionary genetic theory we predicted older fathers' children, all else equal, would be less likely to survive and reproduce, i.e. have lower fitness. In sibling control studies, we find support for negative paternal age effects on offspring survival and reproductive success across four large populations with an aggregate N > 1.4 million. Three populations were pre-industrial (1670–1850) Western populations and showed negative paternal age effects on infant survival and offspring reproductive success. In twentieth-century Sweden, we found minuscule paternal age effects on survival, but found negative effects on reproductive success. Effects survived tests for key competing explanations, including maternal age and parental loss, but effects varied widely over different plausible model specifications and some competing explanations such as diminishing paternal investment and epigenetic mutations could not be tested. We can use our findings to aid in predicting the effect increasingly older parents in today's society will have on their children's survival and reproductive success. To the extent that we succeeded in isolating a mutation-driven effect of paternal age, our results can be understood to show that de novo mutations reduce offspring fitness across populations and time periods.

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