Distal monosomy of the long arm of chromosome 6 (6q25----6qter) inherited by maternal translocation t(6q;17q)

Two half-sisters with distal monosomy of the long arm of chromosome 6 (q25----qter) inherited by maternal translocation t(6q;17q) were investigated. The clinical manifestations of these patients are compared with eight cases reported in the literature for further characterization of the 6q-syndrome. The cytogenetic diagnosis of alterations involving small chromosome fragments and the different origins of this type of deletion are also discussed.     

ARF6 activation by Galpha q signaling: Galpha q forms molecular complexes with ARNO and ARF6

G protein-coupled receptors (GPCRs) are widely expressed hepta-helical receptors with tightly regulated pleiotropic effects. ADP-Ribosylation Factor 6 (ARF6) plays an important role in GPCR trafficking and is the subject of intense research. However, the mechanisms underlying activation and regulation of ARF6 by GPCRs are poorly characterized. Here we report that Galpha(q) signaling leads to the activation of ARF6. Stimulation of the TPbeta receptor triggered ARF6 activation which was completely inhibited by the RGS domain of GRK2 known to specifically bind and sequester Galpha(q). Co-immunoprecipitation studies revealed that ARNO (a guanine nucleotide exchange factor for ARF6) and ARF6 formed complexes preferentially with activated Galpha(q) compared to non-activated Galpha(q). Formation of the Galpha(q) complexes with ARNO and ARF6 was detected early and was optimal after 30 min of receptor stimulation corresponding with the profile of ARF6 activation. Interestingly, binding experiments using purified proteins showed that Galpha(q) interacted directly with ARNO. Galpha(q)-dependent TPbeta receptor-mediated activation of ARF6 resulted in phosphoinositol-4,5-bisphosphate production which was potently inhibited by dominant negative mutants of ARNO and ARF6. Furthermore, our data show that the expression of ARNO and ARF6 promoted, whereas dominant negative mutants of these proteins inhibited the internalization of the TPbeta receptor. This further elucidates our previous data on the PLCbeta- and PKC-independent mechanism involved in Galpha(q)-mediated internalization of the TPbeta receptor. Taken altogether, our results support a novel model where activated Galpha(q) forms molecular complexes with ARNO and ARF6, possibly through a direct interaction with ARNO, leading to ARF6 activation.     

Trisomy 6q syndrome: a case with a < de novo > 6q23 tandem duplication

In this study, we report the combined use of whole and partial chromosome 6 painting probe and YACS probes to define the unbalanced region of a de novo 6q+ marker chromosome. A male patient with peculiar features of < distal 6q trisomy syndrome > showed a direct duplication of 6q23 region. Comparing the phenotype of this child with the phenotype of other < de novo > partial 6q trisomy, we conclude that band 6q23 has an important role in defining 6q trisomy.     

Linkage disequilibrium of plasminogen polymorphisms and assignment of the gene to human chromosome 6q26-6q27

Linkage disequilibrium was observed between newly identified DNA polymorphisms and a previously described protein polymorphism for plasminogen. This finding implies that the two types of polymorphisms describe variation at the same locus. The plasminogen gene was mapped to chromosomal bands 6q26-q27 using somatic-cell hybrids and in situ hybridization. Linkage disequilibrium between protein and DNA polymorphisms has utility in substituting for protein typing in instances where only DNA samples are available, such as from deceased individuals or extinct species. The technique may be useful when cross-hybridizing sequences make the interpretation of Southern blot patterns difficult and may obviate the need for extensive DNA sequencing. In some cases, disequilibrium may provide information useful for determining the appropriate direction for chromosome walks from a marker locus to a target locus.     

Trisomy 6qter resulting from a familial (6;10) (q23;q26) translocation

An infant deceased at 2 months of age was found to have a 46,XY,-10, +der(10),t (6;10) (q23;q26) mat karyotype. Since the clinical findings were similar to those of the trisomy 6qter syndrome, the present observation agrees with the assignment of the 6q23----qter segment as the pathogenetic determiner of this entity.     

A radiation hybrid panel for human Chromosome 6q

A panel of 63 radiation-reduced hybrids has been derived from a mouse cell line containing a neo-marked human Chromosome (Chr) 6, primarily to provide a resource for higher resolution localization of new markers. Hybrids were generated with radiation doses of 40–400 Gy, selected in G418, and were shown by PCR to contain the neo gene. PCR was also used to score the retention of 15 loci that map from 6q13 to q25.2 of the current consensus map plus six other loci assigned to 6q26-q27. An average retention frequency of 27.8% was observed, with the highest frequencies at D6S313 and D6S280 (63.5%) located near the centromere at 6q13, and at D6S283 (68.5%) at 6q16.3-q21, presumably close to the neo integration site. Lowest frequencies (4.8%) were observed for telomeric markers. All markers segregated independently except D6S297 and D6S193. Agreement and some improvement to the current consensus map of 6q was made by mapping 12 loci by the non-parametric statistical method of Falk. In addition, deletion mapping with informative hybrids allowed the ordering of six loci from 6q26 to q27 and permitted some integration of maps of this region.     

Terminal 6q25.3 deletion and abnormal behaviour.

A 10-year-old mentally retarded boy with terminal 6q25 deletion, dysmorphism and striking abnormal behaviour is reported. The main abnormal physical features recorded at different ages consisted of hydrocephalus, axial hypotonia, absence of spontaneous prehension, long face, synophris, hypertelorism with epicanthic folds, internal alternating strabismus, retinal abnormalities with macular degeneration, beaked nose, long philtrum, high-arched palate, lumbar spina bifida, right paravertebral dimple at the upper sacral region, prominent coccyx, broad thumbs and great toes, fetal pads and cryptorchidism. The special behavioural difficulties were made of restlessness, hyperactivity, obsessive compulsive reactions with a self-injurious tendency and episodes of apparently voluntary vomiting crisis concomitant with stress periods. A review of the available literature strongly suggests that individuals with small chromosomal deletions are at high risk of developing behavioural problems.     

Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo

There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n = 6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10(-8)) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p = 1.61×10(-25), within the RASIP1 locus), rs225717 (6q24; p?=?1.25×10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p = 2.15×10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p?=?7.32×10(-16), adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.     

The porcine TTR locus maps to chromosome 6q

The sequence of a cDNA clone encoding porcine transthyretin (prealbumin) was used to develop polymorphic markers for the TTR locus. The single-strand conformation polymorphism (SSCP) detected is caused by a silent AIT mutation in the penultimate coding codon and can also be revealed as a SacI restriction fragment length polymorphism (RFLP). The TTR locus was mapped to chromosome 6q by segregation and linkage analysis with these polymorphisms. This assignment confirms the predictions of homology between human chromosome 18 and pig chromosome 6q2.5-2.6.     

Sublocalization of c-myb to 6q21----q23 by in situ hybridization and c-myb expression in a human teratocarcinoma with 6q rearrangements

We have sublocalized the human proto-oncogene c-myb by applying two different techniques: in situ hybridization of metaphase spreads and chromosome spot hybridization of flow-sorted chromosomes. For this we used a teratocarcinoma cell line carrying specific chromosome translocations involving the two chromosomes 6 and one chromosome 11. The distribution of the c-myb gene copies on the different translocation chromosomes revealed that c-myb is located in the region 6q21----q23. Because of the close proximity of the c-myb locus to the chromosomal breakpoints in the teratocarcinoma, we investigated whether c-myb was implicated in the development of this tumor. No rearrangement, deletion, or amplification of the gene was detected in the teratocarcinoma cells. Furthermore, the level of c-myb expression was comparable to that of other cell lines of nonhematopoietic origin. These results suggest that c-myb was not affected by the translocation and played no significant role in the development of this teratocarcinoma.     

A cosmid library specific for human Chromosome regions 6p21.3 and 6q27

We have explored the potential of irradiation-fusion gene transfer (IFGT) hybrids as a source of well-defined human chromosome fragments from which probes can be derived. Extensive characterization of the IFGT hybrid 4J4 with a full panel of markers from Chromosome (Chr) 6 showed that the human DNA content derives largely from 6p21.3 and 6q27. A cosmid library has been constructed from 4J4 DNA, and 370 recombinants containing human DNA have been isolated and overlapping clones ordered into 20 contigs. Regional localization of representative clones from each contig, determined by fluorescent in situ hybridization (FISH), places 13 contigs in 6q27 and 6 in 6p21.3. Preliminary screening of cDNA libraries with selected cosmids has identified two expressed sequences. Since there are a number of medically important genes in both these regions of human Chr 6 with several disease loci linked to the HLA-A region in 6p21.3 and various tumor suppressor genes to 6q27, this library will provide a valuable resource to aid the isolation of candidate genes for these diseases. In addition, unique markers for detailed physical and genetic mapping of these regions of human Chr 6 can be easily obtained.