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Two Novel Frame Shift, Recurrent and De Novo Mutations in the ITGB2 (CD18) Gene Causing Leukocyte Adhesion Deficiency in a Highly Inbred North African Population.

Fathallah DM, Jamal T, Barbouche MR, Bejaoui M, Hariz MB, Dellagi K - J. Biomed. Biotechnol. (2001)

Bottom Line: We have also characterized a novel Xba1 polymorphic site located at the 5' end of the ITGB2 locus.Family studies showed that the 1497delG mutation segregated with this marker and the intragenic AvaII polymorphic marker, suggesting the presence of a founder effect.In view of the literature published on the molecular genetics of LAD and considering the ethnic origin of the patients studied, our findings confirm the heterogeneity of the mutations causing LAD and point out potential mutational hot spots in the ITGB2 gene.

View Article: PubMed Central - HTML - PubMed

ABSTRACT
We have identified four different mutations causing leukocyte adhesion Deficiency (LAD) in the ITGB2 gene of patients from a highly inbred population. Two were novel single-bp deletions (1497delG and 1920delG) causing frame shift and the two others were the missense mutations G284S and R593C. In our study, the G284S was a recurrent mutation while the R593C occurred de novo. We have also characterized a novel Xba1 polymorphic site located at the 5' end of the ITGB2 locus. Family studies showed that the 1497delG mutation segregated with this marker and the intragenic AvaII polymorphic marker, suggesting the presence of a founder effect. The observation of a heterogeneous spectrum including de novo and recurrent mutations causing LAD in a highly inbred population is rather unexpected. In view of the literature published on the molecular genetics of LAD and considering the ethnic origin of the patients studied, our findings confirm the heterogeneity of the mutations causing LAD and point out potential mutational hot spots in the ITGB2 gene.

No MeSH data available.


Related in: MedlinePlus

Localization of the missense mutations causing LAD, along the CD18 subunit: most of the mutations causing a single amino-acid substitution are clustered in the NH2 domain 250 residues that are highly conserved among the β integrins (β1–β8). A Greek letter indicates each point mutation. Asterisks (*) indicate potential hot spotmutations 1, 2, 3, 4 are the cystein rich repeats, TM = transmembrane domain, CD = cytoplasmic domain.
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Figure 5: Localization of the missense mutations causing LAD, along the CD18 subunit: most of the mutations causing a single amino-acid substitution are clustered in the NH2 domain 250 residues that are highly conserved among the β integrins (β1–β8). A Greek letter indicates each point mutation. Asterisks (*) indicate potential hot spotmutations 1, 2, 3, 4 are the cystein rich repeats, TM = transmembrane domain, CD = cytoplasmic domain.

Mentions: The spectrum of mutations revealed in our patients sample is peculiar in that respect that all the patients exhibited a unique mutation: 1497delG in one allele with only one patient being homozygous for this mutation. The observation of a preferential association between the 1497delG mutation and Ava II+, Xba I+ alleles and the fact that all the patients were born from consanguineous marriages, strongly suggests the presence of a founder effect at the basis of this mutation in our group of patients. It also suggests that this mutation was introduced in this population on an ancestral chromosome, tightly linked to the Ava II+, Xba+ markers. This is the first observation of an association between mutation and polymorphicmarkers in LAD patients. A previously reported haplotype analysis in five patients showed that LAD is not associated with a particular haplotype [19]. However, no informations on the patients ethnic origin or their degree of relatedness were available. The four other patients were compound heterozygous exhibiting two different molecular abnormalities: the 1497delG in one allele and either one of the 1920delG, G284S, or R593C mutations in their second allele. The R593C mutation was already reported in a patient of different ethnic origin as a parentalallele transmitted by descent [17]. However this mutation seems to have arisen de novo in our patient. This mutation occurs at a CPG dinucleotide known to be a highly mutable dinucleotide. Another instance of a de novo in the CD18 gene associated with LAD phenotype was reported [20]. It concerned an A to G transition resulting in the substitution of the asparagine at position 351 by a serine (AAT/AGT). These observations suggest that there might be a predisposition for this type of DNA alteration in the CD18 gene. The report of a patient homozygous for theG284S mutation resulting from a G to A transition (GGC/AGC) [16] suggests that this mutation occurred independently in our patient who is a compound heterozygous G284S-1497delG. The GG dinucleotide affected by this mutation is considered to be a highly mutable dinucleotide according to the classification of thedinucleotides by virtue of their derived relative mutability established by Cooper and Krowczack [21]. Also of interest,is the observation that the mutation causing LAD in human (Japanese patients) and in bovine (Holstein Cattle) [22, 23] affects the same codon: GAC128 coding for a conserved Asparagine suggesting that the codon at this position might be more susceptible to mutagenesis. Other instances of probably recurrent mutations in the CD18 (see Figure 5) are observed and affect residues L149 (L149P: CTA/CCA) (see [16, 24, 25]), G169 (G169R: GGG/AGG) [24, 26], and R586 (R586W: CGT/TGT) [16, 20]. The high propensity to mutate of some of the ITGB2 gene codons, where de novo and recurrent mutations occurred, argues in favor of these sites being potentialmutational “Hot spots.” Interestingly, most of these hot spots are clustered in a 250 amino-acid domain of the CD18 molecule that is highly conserved among the β (β1–8) integrins [12]. This region of the CD18 molecule is sought to be involved in the association of the α and β subunits. Furthermore, the elevated number and the nature of the mutations (de novo, recurrent) affecting the ITGB2 gene as well as their distribution suggest that this gene might be prone to spontaneous mutations.


Two Novel Frame Shift, Recurrent and De Novo Mutations in the ITGB2 (CD18) Gene Causing Leukocyte Adhesion Deficiency in a Highly Inbred North African Population.

Fathallah DM, Jamal T, Barbouche MR, Bejaoui M, Hariz MB, Dellagi K - J. Biomed. Biotechnol. (2001)

Localization of the missense mutations causing LAD, along the CD18 subunit: most of the mutations causing a single amino-acid substitution are clustered in the NH2 domain 250 residues that are highly conserved among the β integrins (β1–β8). A Greek letter indicates each point mutation. Asterisks (*) indicate potential hot spotmutations 1, 2, 3, 4 are the cystein rich repeats, TM = transmembrane domain, CD = cytoplasmic domain.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC129056&req=5

Figure 5: Localization of the missense mutations causing LAD, along the CD18 subunit: most of the mutations causing a single amino-acid substitution are clustered in the NH2 domain 250 residues that are highly conserved among the β integrins (β1–β8). A Greek letter indicates each point mutation. Asterisks (*) indicate potential hot spotmutations 1, 2, 3, 4 are the cystein rich repeats, TM = transmembrane domain, CD = cytoplasmic domain.
Mentions: The spectrum of mutations revealed in our patients sample is peculiar in that respect that all the patients exhibited a unique mutation: 1497delG in one allele with only one patient being homozygous for this mutation. The observation of a preferential association between the 1497delG mutation and Ava II+, Xba I+ alleles and the fact that all the patients were born from consanguineous marriages, strongly suggests the presence of a founder effect at the basis of this mutation in our group of patients. It also suggests that this mutation was introduced in this population on an ancestral chromosome, tightly linked to the Ava II+, Xba+ markers. This is the first observation of an association between mutation and polymorphicmarkers in LAD patients. A previously reported haplotype analysis in five patients showed that LAD is not associated with a particular haplotype [19]. However, no informations on the patients ethnic origin or their degree of relatedness were available. The four other patients were compound heterozygous exhibiting two different molecular abnormalities: the 1497delG in one allele and either one of the 1920delG, G284S, or R593C mutations in their second allele. The R593C mutation was already reported in a patient of different ethnic origin as a parentalallele transmitted by descent [17]. However this mutation seems to have arisen de novo in our patient. This mutation occurs at a CPG dinucleotide known to be a highly mutable dinucleotide. Another instance of a de novo in the CD18 gene associated with LAD phenotype was reported [20]. It concerned an A to G transition resulting in the substitution of the asparagine at position 351 by a serine (AAT/AGT). These observations suggest that there might be a predisposition for this type of DNA alteration in the CD18 gene. The report of a patient homozygous for theG284S mutation resulting from a G to A transition (GGC/AGC) [16] suggests that this mutation occurred independently in our patient who is a compound heterozygous G284S-1497delG. The GG dinucleotide affected by this mutation is considered to be a highly mutable dinucleotide according to the classification of thedinucleotides by virtue of their derived relative mutability established by Cooper and Krowczack [21]. Also of interest,is the observation that the mutation causing LAD in human (Japanese patients) and in bovine (Holstein Cattle) [22, 23] affects the same codon: GAC128 coding for a conserved Asparagine suggesting that the codon at this position might be more susceptible to mutagenesis. Other instances of probably recurrent mutations in the CD18 (see Figure 5) are observed and affect residues L149 (L149P: CTA/CCA) (see [16, 24, 25]), G169 (G169R: GGG/AGG) [24, 26], and R586 (R586W: CGT/TGT) [16, 20]. The high propensity to mutate of some of the ITGB2 gene codons, where de novo and recurrent mutations occurred, argues in favor of these sites being potentialmutational “Hot spots.” Interestingly, most of these hot spots are clustered in a 250 amino-acid domain of the CD18 molecule that is highly conserved among the β (β1–8) integrins [12]. This region of the CD18 molecule is sought to be involved in the association of the α and β subunits. Furthermore, the elevated number and the nature of the mutations (de novo, recurrent) affecting the ITGB2 gene as well as their distribution suggest that this gene might be prone to spontaneous mutations.

Bottom Line: We have also characterized a novel Xba1 polymorphic site located at the 5' end of the ITGB2 locus.Family studies showed that the 1497delG mutation segregated with this marker and the intragenic AvaII polymorphic marker, suggesting the presence of a founder effect.In view of the literature published on the molecular genetics of LAD and considering the ethnic origin of the patients studied, our findings confirm the heterogeneity of the mutations causing LAD and point out potential mutational hot spots in the ITGB2 gene.

View Article: PubMed Central - HTML - PubMed

ABSTRACT
We have identified four different mutations causing leukocyte adhesion Deficiency (LAD) in the ITGB2 gene of patients from a highly inbred population. Two were novel single-bp deletions (1497delG and 1920delG) causing frame shift and the two others were the missense mutations G284S and R593C. In our study, the G284S was a recurrent mutation while the R593C occurred de novo. We have also characterized a novel Xba1 polymorphic site located at the 5' end of the ITGB2 locus. Family studies showed that the 1497delG mutation segregated with this marker and the intragenic AvaII polymorphic marker, suggesting the presence of a founder effect. The observation of a heterogeneous spectrum including de novo and recurrent mutations causing LAD in a highly inbred population is rather unexpected. In view of the literature published on the molecular genetics of LAD and considering the ethnic origin of the patients studied, our findings confirm the heterogeneity of the mutations causing LAD and point out potential mutational hot spots in the ITGB2 gene.

No MeSH data available.


Related in: MedlinePlus