CCR5-Δ32 polymorphism: a possible protective factor for post-stroke depressive symptoms.

Background: A naturally occurring loss-of-function mutation in the gene for C-C chemokine receptor type 5 (CCR5-Δ32) has recently been reported as a protective factor in post-stroke motor and cognitive recovery. We sought to examine whether this mutation also prevented the development of depressive symptoms up to 2 years after a stroke. Methods: Participants were survivors of a first-ever mild to moderate ischemic stroke or transient ischemic attack from the TABASCO prospective study who underwent a 3 T MRI at baseline and were examined by a multiprofessional team 6, 12 and 24 months after the event, including an evaluation of depressive symptoms using the Geriatric Depression Scale. Results: CCR5-Δ32 status and a baseline depression evaluation were available for 435 patients. Compared with noncarriers, CCR5-Δ32 carriers (16.1%) had fewer depressive symptoms at admission (p = 0.035) and at 6 months (p < 0.001), 12 months (p < 0.001) and 24 months (p = 0.006) after the index event. This association remained significant at 6 and 12 months after adjustment for age, sex, education, antidepressant use, ethnicity and the presence of cortical infarcts. These findings were more robust in women. Compared to baseline, depressive symptoms in CCR5-Δ32 noncarriers tended to remain stable or grow worse over time, but in CCR5-Δ32 carriers, symptoms tended to improve. Limitations: A limitation of this study was the exclusion of patients who had a severe stroke or who had pre-stroke depression. Conclusion: Carriers of the CCR5-Δ32 allele had a lower tendency to develop depressive symptoms post-stroke, and this phenomenon was more prominent in women. These findings could have clinical implications; they suggest a mechanism-based treatment target for post-stroke depression. Drugs mimicking this loss-of-function mutation exist and could serve as a novel antidepressant therapy.

Molecular diversity of Glanzmann thrombasthenia in southern India: new insights into mRNA splicing and structure-function correlations of alphaIIbbeta3 integrin (ITGA2B, ITGB3).

The molecular basis of Glanzmann thrombasthenia (GT) was studied in 40 families from southern India. Of 23 identified mutations (13 in the alphaIIb (ITGA2B) gene and 10 in the beta3 (ITGB3) gene), 20 were novel and three were described previously. Three mutations in the beta3 gene-p.Leu143Trp (Leu117Trp), p.Tyr307Stop (Tyr281Stop), and p.Arg119Gln (Arg93Gln)-were detected in 12, three, and two families, respectively, with definite founder effects observed for the first two mutations. Alternative splicing was predicted in silico for the normal variant and a missense variant of the beta3 gene, and for 10/11 frameshift or nonsense mutations in alphaIIb or beta3. The prediction was confirmed experimentally for a c.2898_2902dupCCCCT mutation in exon 28 of the alphaIIb gene that induced exon skipping. Seven out of nine missense mutations substituted highly conserved amino acids buried in the proteins' cores, predicting structural abnormalities. Among these, a beta3 substitution, p.Cys39Gly (Cys13Gly) was found to cause intracellular degradation of the beta3 subunit, in contrast to previous findings that mutations at Cys435, the partner of Cys13 in a disulfide bond, cause constitutive activation of alphaIIbbeta3. The two patients with a beta3 Arg93Gln mutation had normal clot retraction, consistent with a recent finding that this substitution is associated with normal surface expression of alphaIIbbeta3. In conclusion, this study demonstrates that a variety of mutations account for GT in southern Indian patients, provides new insights into mRNA splicing, and highlights the role of specific amino acids in structure-function correlations of alphaIIbbeta3.

Prenatal diagnosis of Glanzmann thrombasthenia.

BACKGROUND: Glanzmann thrombasthenia (GT) is an autosomal recessive disorder of platelet function, which results in major morbidity due to persistent, spontaneous, mucocutaneous bleeding and menorrhagia in women. Platelet transfusions are often needed to control the bleeding. Glanzmann thrombasthenia results from mutations in the genes located on chromosome 17q21-23, encoding the platelet glycoprotein (GP) IIb/IIIa receptor. METHODS: This report describes, for the first time in India, the prenatal diagnosis performed in a family who had a child with GT. As the molecular defect had not been identified at the time of chorionic villus sampling (CVS), prenatal diagnosis was done by linkage assessment. Haplotype analysis was performed using polymorphic markers on chromosome 17q 12-21, which included the dinucleotide repeat polymorphisms (CA)n in BRCA1 gene and locus D17S579 and (CT)n within GP IIIa intron 6, and the known restriction fragment length polymorphism (RFLP) markers Fok I (GP IIb exon 26), Taq I (GP IIIa exon 8) and Sma I (GP IIIa exon 9). The specific mutation in this family was subsequently confirmed. RESULTS: Both parents and the foetus were heterozygous for all the dinucleotide repeat polymorphisms and the affected child was homozygous. Both parents and the affected child were homozygous for Fok I RFLP. The father was heterozygous, and the mother, affected child and foetus were homozygous for Taq I and Sma I. The Fok I RFLP was identical for all the family members and hence did not provide any information for haplotype analysis (foetus not tested). CONCLUSION: The findings from dinucleotide repeat polymorphisms in BRCA1, D17S579, and GP IIIa intron 6 and the Sma I and Taq I RFLPs in GP IIIa strongly suggested that the foetus had inherited the father's mutant and the mother's normal alleles. Hence, the foetus was diagnosed to be a heterozygous carrier of GT by haplotype analysis. A private sequence alteration was later identified in the affected child in GP IIIa IVS1 (-14C --> A). The parents and foetus were heterozygous for this mutation. This confirmed the findings of the haploytpe analysis.