Skip Navigation

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (16)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Oron-Karni, V.
Right arrow Articles by Oppenheim, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Oron-Karni, V.
Right arrow Articles by Oppenheim, A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Human Molecular Genetics Pages 881-885

A novel mechanism generating short deletion/insertions following slippage is suggested by a mutation in the human [alpha]2-globin gene
Introduction
Results
Discussion
Materials And Methods
   Subjects
   Genomic digest and Southern blots
   PCR and sequencing analysis
   Mutation database search
Acknowledgements
References
Table

A novel mechanism generating short deletion/insertions following slippage is suggested by a mutation in the human [alpha]2-globin gene

A novel mechanism generating short deletion/insertions following slippage is suggested by a mutation in the human [alpha] 2 -globin gene Varda Oron-Karni, Dvora Filon, Deborah Rund and Ariella Oppenheim*

Department of Hematology, Hebrew University-Hadassah Medical School and Hadassah University Hospital, Jerusalem 91120, Israel

Received January 31, 1997; Revised and Accepted March 12, 1997

A novel mechanism generating short deletion/insertions is described based on a mutation in the human [alpha]2-globin gene. A deletion of 9 bp (codons 39-41) is replaced by an eight nucleotide insertion, duplicating the adjacent downstream sequence. We propose that the mutation arose by slipped strand mispairing (SSM), creating a single-stranded loop, followed by DNA elongation, strand breathing and the formation of a mismatch bubble. An extensive literature search has revealed six additional deletion/insertion mutations in humans in which the inserted nucleotides come from the same DNA strand. Our model explains all six mutations, suggesting that rearrangement of a mismatch loop or bubble during DNA replication may be not uncommon.

INTRODUCTION

Human mutations provide a rich source of information for the study of mechanisms of genomic instability. Over 15 years ago it was first suggested by Efstratiadis et al. (1 ) that slipped strand mispairing (SSM) is enhanced by short (2 -8 ) direct repeats, which may induce short deletions in mammalian DNA. SSM has since been suggested to play an important role in the expansion of trinucleotide repeats, causing a number of neurodegenerative disorders (Fragile X, spinocerebellar ataxia, Huntington's disease and others) (2 ,3 ). In addition, the size variation of microsatellite repeats, seen as polymorphic markers, is also thought to result from SSM. SSM probably also leads to the variability in microsatellite repeats seen in tumor cells, reflecting the high degree of genomic instability in those tissues (4 ,5 ). Thus SSM appears to occur both in germline and in somatic cells.

Slippage of the replication fork is not in itself sufficient to explain the more complex mutations in which small deletions are combined with insertions. Here we describe a deletion/ duplication mutation in the human [alpha]2-globin gene which allowed us to formulate a novel mechanism accounting for the generation of this mutation, as well as a number of other additional human mutations.

The human [alpha]-globin cluster is composed of two functional genes ([alpha]2 and [alpha]1) which are located in a duplicated region of 4 kb. Unequal crossing over is presumed to be the cause of the common genetic lesions (single gene deletions and triplications), with point mutations being less frequent (6 ,7 ). Such molecular lesions lead to [alpha]-thalassemia by impairing production of the [alpha]-globin chains of the hemoglobin tetramer. The various molecular lesions in heterozygotes lead to a wide range of phenotypes, which may be diagnosed by hematological criteria. In general, the red blood cells are found to have microcytosis (low mean corpuscular volume, MCV) and hypochromia (low mean corpuscular hemoglobin, MCH), and mild anemia may be noted (6 ,7 ). The severe forms of [alpha]-thalassemia are HbH disease, with three non-functional [alpha]-globin genes, causing moderate congenital anemia, and hydrops fetalis, with no functional [alpha]-globin genes, causing intrauterine death.

RESULTS

Analysis of the DNA of patient 1 for gross rearrangements in the [alpha]-globin gene by Southern analysis demonstrated heterozygosity for a common single [alpha]-globin gene deletion (genotype -[alpha]3.7/[alpha][alpha]). A normal [alpha]-globin gene configuration ([alpha][alpha]/[alpha][alpha]) was found for patient 2 (data not shown). These results are consistent with the milder phenotype of patient 2. However, they do not fully account for the low MCV and MCH values of the patients, suggesting the presence of point mutation(s). Screening for point mutations known in our population was unrevealing.

Sequencing of both strands of the [alpha]2-globin gene revealed a novel deletion/duplication mutation in both patients (Fig. 1 ). A deletion of 9 bp (codons 39-41, exon 2) is replaced by an insertion of eight nucleotides, which represents a duplication of the adjacent downstream sequence. The mutation changes the reading frame, resulting in a termination signal, TGA, 10 codons downstream.+


Figure 1. Deletion/duplication mutation in exon 2 of the [alpha]2-globin gene. (A) Physical map of the [alpha]-globin locus and location of the PCR primers. The -[alpha]3.7 single gene deletion results from unequal crossing over between the [alpha]2 and [alpha]1 genes. (B) Sequence analysis of the PCR product of patient 1. The boxes enclose nucleotides which are duplicated or deleted in the mutant and normal control, respectively. Patient 1 carries a single [alpha]2 allele, as the other chromosome carries the -[alpha]3.7 deletion. (C) Nucleotide sequence of the normal and mutant alleles (`sense' strand). Underlined, ACC repeats; bold underline, deleted nucleotides; upper case letters, duplicated nucleotides. The CCTG motif is shown in bold. The sequence shown is derived from GenBank accession no. J00153, coordinates 6915-6972.

Examination of the surrounding DNA sequence reveals several features previously reported to be associated with gene rearrangements. The tetranucleotide sequence, CCTG, present in the proximity of 25% of human gene deletions (8 ) is also present in two repeats on both sides of the rearrangement (Fig. 1 C). In addition, the deletion/duplication is present within a region of high GC content, suggested to be associated with a high deletion frequency in prokaryotic DNA (9 ). Three ACC direct repeats present within 12 bp (and a fourth, located 16 bp downstream) may have caused the mispairing and slippage that initiated the mutagenic event.


Figure 2. A model for the generation of the deletion/duplication. The sequence shown is derived from GenBank accession no. J00153, coordinates 6930-6965. The deleted nucleotides are underlined. The duplicated sequences are marked by a line above. Direct repeats are shown in bold.

DISCUSSION

The deletion/duplication mutation within the coding sequence, which abolishes the expression of the [alpha]2-globin gene, together with the other molecular findings, accounts for the hematological parameters of both patients. Most of the [alpha]-thalassemia point mutations reported to date were found in the [alpha]2-globin gene. This is presumably because the [alpha]2-globin gene is expressed at a rate 3-fold higher than the [alpha]1 gene and therefore mutations in [alpha]2 affect the phenotype to a greater extent (7 ). The mutation discovered in this study is rare, and has been found so far only in two unrelated individuals of Yemenite-Jewish origin, who probably have a common ancestor.

Examination of the sequence led us to propose that the deletion and duplication have occurred sequentially in the generation of this mutation (Fig. 2 ). According to our model, the first event was slippage leading to a nine nucleotide deletion induced by two of the three ACC direct repeats (step b). Following extension by DNA polymerase (step c), we postulate that the slippage loop has been opened up (strand breathing), followed by incorrect pairing downstream to the first slippage event, resulting in the creation of a mismatch bubble (step d). Further DNA elongation resulted in duplication of eight nucleotides (step e). The next round of DNA replication presumably led to the synthesis of one normal and one mutant DNA duplex. Our model suggests that SSM, followed by strand breathing and replacement of the slippage loop by a mismatch bubble, caused the deletion/duplication.

Table 1 . Summary of known human deletion/insertion mutations
 

 Gene

 Deletion/insertion

 Surrounding sequencea

 Reference
1.

 [alpha]-Globin

 -9/+8

 Direct repeats, 60% GC

 Present study
2.

 [beta]-Globin

 -7/+10

 Direct repeats, 56% GC

 (18)
3.

 [beta]-Globin

 -10/+4

 Direct repeats, 56% GC

 (19)
4.

 Collagen

 -11/+25

 Direct repeats, 66% GC

 (20)
5.

 IDUA

 -22/+10

 Direct repeats, 70% GC

 (21)
6.

 GALC

 -12/+3

 Direct repeats, 44% GC

 (22)
7.

 RBI

 -5/+19

 Direct repeats, 29% GC

 (23)
8.

 [beta]-Globin

 -4/+5b

 Direct repeats, 58% GC

 (24)
9.

 Glycoprotein IIb

 -6/+31

 Direct repeats and
symmetric elements, 52% GC		 (25)
10.

 PCCB

 -14/+12

 Inverted repeats, 55% GC

 (26,27)
11.

 LDL receptor

 -9/+6

 Inverted repeats, 61% GC

 (28)
12.

 gp91-phox

 -3/+15

 Inverted repeats, 56% GC

 (29)
13.

 FXIIIa

 -2/+6

 Inverted repeats, 49% GC

 (30)
14.

 HPRT

 -5/+6

 Inverted repeats, 42% GC

 (31)

aEncompassing 20 bp upstream and 20 bp downstream.
bThere is an additional 11 bp deletion, 8 bp downstream of the breakpoint of the first deletion.

A number of short deletion/insertion mutations in humans have been described. An extensive literature search has revealed 13 such additional mutations (a total of 14, Table 1 ), almost all under 20 bp. Direct repeats, suggesting slippage, were found in eight of these (Table 1 , nos 1-8). In seven of them, the inserted nucleotides come from a neighboring sequence on the same DNA strand. We have asked whether the mechanism described above may also account for the six additional mutations (nos 2-7 in Table 1 ). Detailed analysis of their sequences (available upon request) demonstrated that they may indeed be explained by the model. The common features are slippage, the formation of a single-stranded loop and DNA extension, followed by strand breathing and the creation of a double-stranded mismatch bubble. In mutations no. 2 and no. 4 there is, in addition, a single base substitution, and in mutation no. 3 there is an insertion of a single C. These additional changes support the notion that impaired proofreading plays a role in the generation of small deletions or insertions. Our model suggests that mutation no. 4 was created by a deletion followed by two duplication events, resulting in two insertions, of 11 and 10 nucleotides respectively. In mutation no. 7, which was found in tumor cells, we assumed an insertion of a T as a prior event. Such single base deletions or insertions are common in tumor cells (10 ). In addition, in this mutation (no. 7) the model suggests two slippage events each resulting in a nine nucleotide insertion, followed by the deletion of five nucleotides.

In mutation no. 8, the inserted sequence comes from the complementary DNA strand, implying the participation of another type of secondary structure. This mutation includes an additional 11 bp deletion, eight nucleotides downstream of the breakpoint of the first deletion. Mutation no. 3 occurred seven nucleotides downstream of no. 8, suggesting enhanced instability of this region.

The other six mutations, nos 9-14, are located in regions of symmetric elements or inverted repeats (Table 1 ) and thus may have arisen by a different type of mechanism, which involves hairpin or stem-loop structures, or Moebius loops (8 ,11 ). In addition to the presence of direct or inverted repeats, most of the mutations are present within a region of high GC content (Table 1 ), emphasizing the important role of the surrounding DNA sequence in the genesis of this type of mutational event.

In conclusion, we propose that strand breathing may occur following slipped mispairing, probably relieving local constraints on the single-stranded loop. It has been suggested that the polymerase pauses when it encounters a complex DNA configuration such as a triple helix (12 -14 ). Such a pause may allow the replication fork to undergo strand breathing and reannealing. If this occurs after some extension has taken place, the DNA at the replication fork may attain any of several alternative configurations. The specific configuration present when DNA elongation ensues will determine whether the outcome of the SSM event would be a simple short deletion (or a duplication) or a more complex deletion/insertion. Therefore, only some of the SSM events will result in both deletion and insertion. It should be noted that for microsatellites, deletion/insertion events would be indistinguishable from simple deletions or duplications. Thus, this mechanism may be more frequent than suggested by the total number of deletion/insertion mutations seen to date. This mechanism is probably restricted to a size range which is determined by specific properties of the replication machinery.

MATERIALS AND METHODS

Subjects

Two unrelated individuals of Yemenite-Jewish origin were referred for evaluation of unexplained mild microcytic anemia. Their hematological data was compatible with an [alpha]-thalassemia trait. Patient 1 is 20 years old. Her hematological data is compatible with an [alpha]-thalassemia trait (Hb 11.1 g/dl, MCV 66.8 fl, MCH 19.8 pg). Patient 2 is 13 years old. Her hematological data is also compatible with an [alpha]-thalassemia trait, with a milder phenotype (Hb 12.6 g/dl, MCV 74.5 fl, MCH 23.6 pg). In both, iron deficiency and a [beta]-thalassemia trait were excluded.

Complete blood counts were performed on a Coulter S Plus IV analyzer.

Genomic digest and Southern blots

DNA was isolated from peripheral blood leukocytes according to standard procedures (15 ,16 ). Southern analysis was performed using BglII digestion, with a [zeta]-globin-specific probe (17 ).

PCR and sequencing analysis

PCR of the complete [alpha]2-globin gene was performed with Taq DNA polymerase (Appligene), using the conditions recommended by the manufacturer, with ~1 [mu]g of genomic DNA. The amplification cycle consisted of 1 min at 94oC, 1.5 min at 62oC and 1.5 min at 72oC. Thirty five cycles of PCR were usually sufficient. Primers were P56: 5'-CCCCAAGCATAAACCCTGGC and P52: 5'-CCTCCATTGTTGGCACATTCC, yielding a product of 922 bp. The PCR product was isolated following electrophoresis on a 1% low-melting agarose gel. The band was removed and kept frozen. Prior to sequencing, the agarose was melted at 68oC and 14 [mu]l was used for each reaction. Direct sequencing was performed using the internal primers P57: 5'-ACAGGCCACCCTCAACCGTC (sequencing the `sense' strand) and P66: 5'-CTTCTTGCCGTGGCCCTTAAC (for the `antisense' strand), with Sequenase Version 2 (USB).

Mutation database search

A literature search was performed using Medline Subset Query Form with the following key words (including search of Mesh headings): `insertion deletion' and `human' and `base sequence' but not `polymorphism'. Out of 419 titles retrieved, we found 13 which were relevant.

ACKNOWLEDGEMENTS

We thank Dr Amos B. Oppenheim for fruitful discussions.This work was supported by grant 91-00055 from the United States-Israel Binational Science Foundation (BSF), Jerusalem; and by grants 2310 and 3172 from the Ministry of Health, Israel.

REFERENCES

1 Efstratiadis, A., Posakony, J.W., Maniatis, T., Lawn, R.M., O'Connell, C., Spritz, R.A., DeRiel, J.K., Forget, B.G., Weissman, S.M., Slightom, J.L., Blechl, A.E., Smithies, O., Baralle, F.E., Shoulders, C.C. and Proudfoot, N.J. (1980) The structure and evolution of the human beta-globin gene family. Cell, 21,653-668. MEDLINE Abstract

2 Bates, G. and Lehrach, H. (1994) Trinucleotide repeat expansions and human genetic disease. BioEssays, 16,277-284. MEDLINE Abstract

3 Eichler, E.E., Holden, J.J.A., Popovich, B.W., Reiss, A.L., Snow, K., Thibodeau, S.N., Richards, C.S., Ward, P.A. and Nelson, D.L. (1994) Length of uninterrupted CGG repeats determines instability in the FMR1 gene. Nature Genet., 8,88-94. MEDLINE Abstract

4 Wooster, R., Cleton-Jansen, A.-M., Collins, N., Mangion, J., Cornelis, R.S., Cooper, C.S., Gusterson, B.A., Ponder, B.A.J., von Diemling, A., Wiestler, O.D., Cornelisse, C.J., Devilee, P. and Stratton, M.R. (1994) Instability of short tandem repeats (microsatellites) in human cancers. Nature Genet., 6,152-156. MEDLINE Abstract

5 Ben-Yehuda, D., Krichevsky, S., Caspi, O., Rund, D., Polliack, A., Abeliovich, D., Zelig, O., Yahalom, V., Paltiel, O., Or, R., Peretz, T., Ben-Neriah, S., Yehuda, O. and Rachmilewitz, E.A. (1996) Microsatellite instability and p53 mutations in therapy-related leukemia suggests mutator phenotype. Blood, 88,4296-4303. MEDLINE Abstract

6 Higgs, D.R., Vickers, M.A., Wilkie, A.O., Pretorius, I.M., Jarman, A.P. and Weatherall, D.J. (1989) A review of the molecular genetics of the human alpha-globin gene cluster. Blood, 73,1081-1104. MEDLINE Abstract

7 Higgs, D.R. (1993) Alpha-thalassaemia. Baillieres Clin. Haematol., 6,117-150. MEDLINE Abstract

8 Krawczak, M. and Cooper, D.N. (1991) Gene deletions causing human genetic disease: mechanisms of mutagenesis and the role of the local DNA sequence environment. Hum. Genet., 86,425-441. MEDLINE Abstract

9 Singer, B.S. and Westlye, J. (1988) Deletion formation in bacteriophage T4. J. Mol. Biol., 202,233-243. MEDLINE Abstract

10 Karran, P. and Bignami, M. (1994) DNA damage tolerance, mismatch repair and genome instability. BioEssays, 16,833-839. MEDLINE Abstract

11 Cooper, D.N. and Krawczak, M. (1991) Mechanisms of insertional mutagenesis in human genes causing genetic disease. Hum. Genet., 87,409-415. MEDLINE Abstract

12 Baran, N., Lapidot, A. and Manor, H. (1987) Unusual sequence element found at the end of an amplicon. Mol. Cell. Biol., 7,2636-2640. MEDLINE Abstract

13 Kang, S., Ohshima, K., Shimizu, M., Amirhaeri, S. and Wells, R.D. (1995) Pausing of DNA synthesis in vitro at specific loci in CTG and CGG triplet repeats from human hereditary disease genes. J. Biol. Chem., 270,27014-27021. MEDLINE Abstract

14 Little, R.D. and Schildkraut, C.L. (1995) Initiation of latent DNA replication in the Epstein-Barr virus genome can occur at sites other than the genetically defined origin. Mol. Cell. Biol., 15,2893-2903. MEDLINE Abstract

15 Goossens, M. and Kan, Y.W. (1981) DNA analysis in the diagnosis of hemoglobin disorders. Methods Enzymol., 76,805-817. MEDLINE Abstract

16 Miller, S.A., Dykes, D.D. and Polesky, H.F. (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res., 16,1215. MEDLINE Abstract

17 Melis, M.A., Pirastu, M., Galanello, R., Furbetta, M., Tuveri, T. and Cao, A. (1983) Phenotypic effect of heterozygous alpha and [beta]o-thalassemia interaction. Blood, 62,226-229. MEDLINE Abstract

18 Plaseska, D., Dimovski, A.J., Wilson, J.B., Webber, B.B., Hume, H.A. and Huisman, T.H.J. (1991) Hemoglobin Montreal: a new variant with an extended [beta] chain due to a deletion of Asp, Gly, Leu at positions 73, 74, and 75, and an insertion of Ala, Arg, Cys, Gln at the same location. Blood, 77,178-181. MEDLINE Abstract

19 Oner, R., Oner, C., Wilson, J.B., Tamagnini, G.P., Ribeiro, L.M. and Huisman, T.H. (1991) Dominant beta-thalassaemia trait in a Portuguese family is caused by a deletion of (G)TGGCTGGTGT(G) and an insertion of (G)GCAG(G) in codons 134, 135, 136 and 137 of the beta-globin gene. Br. J. Haematol., 79,306-10.

20 Hilal, L., Rochat, A., Duquesnoy, P., Blanchet-Bardon, C., Wechsler, J., Martin, N., Christiano, A.M., Barrandon, Y., Uitto, J., Goossens, M. and Hovnanian, A. (1993) A homozygous insertion-deletion in the type VII collagen gene (COL7A1) in Hallopeau-Siemens dystrophic epidermolysis bullosa. Nature Genet., 5,287-292. MEDLINE Abstract

21 Moskowitz, S.M., Tieu, P.T. and Neufeld, E.F. (1993) A deletion/insertion mutation in the IDUA gene in a Libyan Jewish patient with Hurler syndrome (Mucopolysaccharidosis IH). Hum. Mutat., 2,71-73. MEDLINE Abstract

22 Tatsumi, N., Inui, K., Sakai, N., Fukushima, H., Nishimoto, J., Yanagihara, I., Nishigaki, T., Tsukamoto, H., Fu, L., Taniike, M. and Okada, S. (1995) Molecular defects in Krabbe disease. Hum. Mol. Genet., 4,1865-1868. MEDLINE Abstract

23 Shimizu, T., Toguchida, J., Kato, M.V., Kaneko, A., Ishizaki, K. and Sasaki, M.S. (1994) Detection of mutations of the RBI gene in Retinoblastoma patients by using exon-by-exon PCR-SSCP analysis. Am. J. Hum. Genet., 54,793-800. MEDLINE Abstract

24 Thein, S.L., Hesketh, C., Taylor, P., Temperley, I.J., Hutchinson, R.M., Old, J.M., Wood, W.G., Clegg, J.B. and Weatherall, D.J. (1990) Molecular basis for dominantly inherited inclusion body beta-thalassemia. Proc. Natl Acad. Sci. USA, 87,3924-3928. MEDLINE Abstract

25 Peretz, H., Rosenberg, N., Usher, S., Graff, E., Newman, P.J., Coller, B.S. and Seligsohn, U. (1995) Glanzmann's thrombasthenia associated with deletion-insertion and alternative splicing in the glycoprotein IIb gene. Blood, 85,414-420. MEDLINE Abstract

26 Tahara, T., Kraus, J.P. and Rosenberg, L.E. (1990) An unusual insertion/deletion in the gene encoding the [beta]-subunit of propionyl-CoA carboxylase is frequent mutation in Caucasian propionic acidemia. Proc. Natl Acad. Sci. USA, 87,1372-1376. MEDLINE Abstract

27 Lamhonwah, A., Troxel, C.E., Schuster, S. and Gravel, R.A. (1990) Two distinct mutations at the same site in the PCCB gene in propionic acidemia. Genomics, 8,249-254. MEDLINE Abstract

28 Yamakawa-Kobayashi, K., Kobayashi, T., Yanagi, H., Shimakura, Y., Satoh, J. and Hamaguchi, H. (1994) A novel complex mutation in the LDL receptor gene probably caused by the simultaneous occurrence of deletion and insertion in the same region. Hum. Genet., 93,625-628. MEDLINE Abstract

29 Ariga, T., Sakiyama, Y. and Matsumoto, S. (1995) A 15-base pair (bp) palindromic insertion associated with a 3-bp deletion in exon 10 of the gp91-phox gene, detected in two patients with X-linked chronic granulomatous disease. Hum. Genet., 96,6-8. MEDLINE Abstract

30 Anwar, R., Stewart, A.D., Miloszewski, K.J.A., Losowsky, M.S. and Markham, A.F. (1995) Molecular basis of inherited factor XIII deficiency: identification of multiple mutations provides insights into protein function. Br. J. Haematol., 91,728-735. MEDLINE Abstract

31 Gibbs, R.A., Nguyen, P., McBride, L.J., Koepf, S.M. and Caskey, C.T. (1989) Identification of mutations leading to Lesch-Nyhan syndrome by automated direct DNA sequencing of in vitro amplified cDNA. Proc. Natl. Acad. Sci. USA, 86,1919-1923. MEDLINE Abstract

*To whom correspondence should be addressed. Tel: +972 2 677 6753; Fax: +972 2 642 3067; Email: ariella@cc.huji.ac.il

-->
This page is maintained by OUP admin. Last updated Mon May 12 18:10:04 BST 1997. Part of the OUP Journals World Wide Web service. Copyright Oxford University Press, 1996


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 IOVSHome page
C. Vijayasarathy, L. Ziccardi, Y. Zeng, N. Smaoui, R. C. Caruso, and P. A. Sieving
Null Retinoschisin-Protein Expression from an RS1 c354del1-ins18 Mutation Causing Progressive and Severe XLRS in a Cross-Sectional Family Study
Invest. Ophthalmol. Vis. Sci., November 1, 2009; 50(11): 5375 - 5383.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurol. Neurosurg. PsychiatryHome page
C Mauro, G Giaccone, G Piscosquito, A Lavorgna, M Nigro, G Di Fede, A Leonardi, C Coppola, S Formisano, F Tagliavini, et al.
A novel insertional mutation in the prion protein gene: clinical and bio-molecular findings
J. Neurol. Neurosurg. Psychiatry, December 1, 2008; 79(12): 1395 - 1398.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
S. M. Rich and F. J. Ayala
Population structure and recent evolution of Plasmodium falciparum
PNAS, June 20, 2000; 97(13): 6994 - 7001.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (16)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Oron-Karni, V.
Right arrow Articles by Oppenheim, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Oron-Karni, V.
Right arrow Articles by Oppenheim, A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?