eNOS gene Glu298Asp and 4b/a polymorphisms are associated with renal function parameters in Mexican patients with Fabry disease.

Fabry disease (FD) is an inherited X-linked lysosomal disease that causes renal failure in a high percentage of affected individuals. The eNOS gene encodes for endothelial nitric oxide synthase, which plays an important role in glomerular hemodynamics. This gene has two main polymorphisms (Glu298Asp and 4b/a) that have been studied in the context of many different diseases, including those involving cardiovascular and renal alterations. Considering the lack of information regarding eNOS variants and FD, we investigated whether there were associations between eNOS genetic variants and renal function parameters in Mexican patients with FD and renal impairment. In total, 15 FD patients with renal alterations were included in the present study, and associations between eNOS polymorphisms and renal function parameters (urea, creatinine, and GFR) were evaluated. The Asp298 and 4a alleles of the eNOS gene were found to be significantly associated with increased levels of urea and creatinine, and a decreased glomerular filtration rate in FD patients, and this association behaved in a co-dominant fashion. Our results coincide with previous reports showing an association between these polymorphisms and kidney disease, and along with other studies regarding their role in the nitric oxide pathway, suggest that these variants affect the severity of nephropathy in patients with FD.

Calpain-10 gene polymorphisms and risk of type 2 diabetes mellitus in Mexican mestizos.

The calpain-10 gene is expressed primarily in tissues important in glucose metabolism; thus, some of its polymorphisms have been associated with type 2 diabetes. In this study, we examined the association between the calpain-10 single-nucleotide polymorphism (SNP)-43, SNP-19, and SNP-63 and type 2 diabetes in Mexican mestizos. We included 211 patients and 152 non-diabetic subjects. Polymerase chain reaction was used to identify alleles. We compared allele, genotype, haplotype, and diplotype frequencies between both groups and used the chi-square test to calculate the risk. The allele frequency of SNP-43 allele 1 was 70% in controls and 72% in patients; the GG, GA, and AA genotype frequencies were 48.7, 42.8, and 8.5% in controls and 51.2, 41.7, and 7.1% in patients, respectively. For SNP- 19, the prevalence of allele 1 (2R) was 32% in controls and 39% in patients. In controls, homozygosity (2R/2R) was 10.5%, heterozygosity was 42.8%, and 3R/3R was 46.7%; in cases, these values were 13.3, 50.7, and 36.0%, respectively. For SNP-63, the frequency of allele 1 was 87% in controls and 83% in patients; genotype frequencies in controls were 75.7% (CC), 23% (CT), and 1.3% (TT), and were 69.7, 27.5, and 2.8%, respectively for the cases. Genotype distributions were consistent with Hardy-Weinberg equilibrium. No significant intergroup differences for allele, genotype, haplotype, or diplotype frequencies were observed. We found no association between these polymorphisms and diabetes. However, our sample size was small, so the role of calpain-10 risk alleles should be further examined.

Pure 9p trisomy derived from a terminal balanced unreciprocal translocation.

The 9p trisomy is a relatively frequent disorder, while pure 9p trisomies are less frequent and usually derived from 9;22 translocations, duplications or 9p extra chromosomes. Here we report a patient with pure trisomy 9p derived from a terminal balanced unreciprocal translocation. The patient derived to the genetic service by psychomotor delay, presented at 2 years and 11 months: short stature, open anterior fontanelle, dysplastic ears, facial dysmorphisms, long and broad first toes with hypoplastic nails, central nervous system and skeletal alterations. The patient karyotype was: 46,XY,der(10)t(9;10) (p13.1;qter)mat while the mother karyotype was: 46,XX,t(9;10)(p13.1;qter). The presence of the subtelomeric region of 10q showed by FISH as well as the duplication of 9p subtelomere was further confirmed with multiplex ligation dependent probe amplification (MLPA) for the subtelomeric region of all chromosomes. The mechanism of formation seems to be due to a telomere break in 10q leading to loss of telomeric functions, permitting the 9p fusion; this has been supported with molecular probes showing telomere shortening in interstitial telomeric repeats, which are unable to prevent chromosome fusion. This is one of the few cases reported with terminal translocations (not jumping) preserving the subtelomeric region and highlights the importance of subtelomeric probes in terminal arrangements, and the utility of molecular probes, such as MLPA in defining this kind of abnormalities. In the clinical context, the patient presented a high proportion of 9p trisomy features which is expected considering the large 9p segment involved and the presence of the critical region 9p22.

A non-sense mutation in the corneodesmosin gene in a Mexican family with hypotrichosis simplex of the scalp.

BACKGROUND: Hypotrichosis simplex of the scalp (HSS; MIM 146520) is a rare autosomal dominant form of non-syndromic alopecia that affects men and women equally. Up to now, only a small number of families with HSS have been reported. The affected individuals experience a diffuse progressing hair loss from childhood to adulthood that is confined to the scalp. Recently, HSS has been mapped to the short arm of chromosome 6 (6p21.3), allowing mutations in the corneodesmosin gene (CDSN) to be identified as the cause of the disorder. To date, two stop mutations have been found in three unrelated families with HSS of different ethnic origin. OBJECTIVES: To describe the first HSS-family with Latin American (Mexican) background comprising 6 generations and to identify a mutation in the CDSN gene. PATIENTS/METHODS: The patients were examined by a clinician and blood samples were taken. After DNA extraction, sequencing analysis of the CDSN gene and restriction enzyme analysis with PsuI were performed. RESULTS: By direct sequencing of the two exons of the CDSN gene, a nonsense mutation was identified in the index patient in exon 2, resulting in a premature stop codon (Y239X). The mutation co-segregates perfectly in the family with the disease and was not found in 300 control chromosomes using a restriction enzyme analysis with PsuI. CONCLUSIONS: A nonsense mutation was identified in the first family with HSS of Latin American ethnical background. Our data provide molecular genetic evidence for a 3rd stop mutation in exon 2 of the CDSN gene being responsible for HSS. All to date known nonsense mutations responsible 3 for HSS are clustered in a region of 40 amino acids which is in accordance with a dominant negative effect conferred by aggregates of truncated CDSN proteins.

Increased expression of AML1-a and acquired chromosomal abnormalities in childhood acute lymphoblastic leukemia.

A semi-quantitative expression analysis of both AML1-a and AML1-total was performed by RT-PCR in 19 children with acute lymphoblastic leukemia (ALL) at diagnosis. AML1-a expression was assessed in 16 bone marrow (BM) and 13 peripheral blood (PB) samples whereas AML1-total was assessed in 17 BM and 16 PB samples. These analyses were also carried out in 15 PB samples of healthy controls. In addition, 18/19 patients were karyotyped: 11 had an unmodified constitutional karyotype (CK) and seven exhibited acquired chromosomal abnormalities (ACA). The expression of AML1-a was significantly increased in BM and PB when compared with the controls (p < 0.013 and p < 0.035, respectively). A significant increase was found in the expression of AML1-a in BM of the ACA group compared with the CK group (p < 0.0009). The expression of AML1-a in BM and PB showed a significant increase in the ACA group compared with controls (p < 0.00001 and p < 0.012, respectively); in contrast, the CK group did not differ from the controls. These observations may mean that the increase of AML1-a favours the progression of leukemia.

Paternal isodisomy 7q secondary to monosomy 7 at recurrence in a Down syndrome child with acute myelogenous leukemia.

We report a boy with Down syndrome and leukemia who acquired uniparental isodisomy of chromosome 7q as a secondary chromosomal change during recurrence of the disease. His karyotype before therapy was 46,XY,der(1)t(1;1)(p36;q32),-7,+21c/46,idem,del(9)(p22), whereas at recurrence it was 46,XY,der(1)t(1;1)(p36;q32,-7,der(7)(qter-->p22 through pter::q10-->qter),del(9)(p22),+21c/47,XY,+21c. By using polymerase chain reaction amplification of D7S493 and D7S527 markers, we identified the loss of the maternal chromosome 7 with a consequent paternal isodisomy in the clone with dup7q. This rearrangement could be implicated in the progression of the disease by causing (1) nullisomy for a gene or genes located on 7p22-->pter, (2) functional double doses of exclusively paternal expressed genes, and (3) restoration of the effects produced by haploinsufficiency of biparental expressed genes.