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Objectives: (1) To detect interferon regulatory factor 6 gene (IRF6) mutations in newly recruited Van der Woude syndrome (VWS) and popliteal pterygium syndrome (PPS) families. (2) To test for association, in nonsyndromic cleft lip and/or cleft palate (NSCL/P) and in VWS/PPS families, the single nucleotide polymorphism (SNP) rs642961, from the IRF6 enhancer AP-2 alpha region, alone or as haplotype with rs2235371, a coding SNP (Val274Ile). Design: IRF6 mutation screening was performed by direct sequencing and genotyping of rs642961 and rs2235371 by TaqMan technology. Patients: Seventy-one Swedish NSCL/P families, 24 Finnish cleft palate (CP) families, and 24 VWS/PPS families (seven newly recruited) were studied. Results: Allelic and genotypic frequencies in each phenotype were compared to those of the controls, and no significant difference could be observed. IRF6 gene mutation was detected in six of the seven new VWS/PPS families. Association analysis of the entire VWS/PPS sample set revealed the A allele from rs642961 to be a risk allele. Significant association was detected in the Swedish CP subset of our NSCL/P collection where the G-C haplotype for rs642961-rs2235371 were at risk (P = .013). Conclusions: Our results do not support the previously reported association between the A allele of rs642961 and the NSCL phenotype. However, in the VWS/PPS families, the A allele was a risk allele and was, in a large majority (>80%), transmitted on the same chromosome as the IRF6 mutation., AuthorCount:8

Objective: To assess real long-term varicose vein recurrence and patient satisfaction following surgical intervention with combined subfascial endoscopic perforator surgery (SEPS) and superficial venous surgery. Method: Prospective consecutive case study (C3-C4). Patients were included March 1993 to September 1998 and 83/104 legs of 80/100 patients were re-assessed 2008; 71 legs underwent duplex ultrasound scanning (DUS). Results: The median follow up was 12 years (range 10-14). Twelve patients/legs had undergone additional vein surgery during follow-up. Incompetent lower leg perforators were noted in 18/71 limbs (25%). Following groin surgery 23/51 (45%) showed a duplex detected groin recurrence, neovascularization dominated 18/23. In legs where primary great saphenous vein (GSV) surgery had been performed, groin recurrence was found in 14/37 (38%). Previously unknown deep vein incompetence was detected in 14/71 legs (20%), six had axial reflux. The correlation between DUS-detected recurrence and remaining symptoms and cosmetic result was low. The overall satisfaction was high, 70/82 (85%). Patient satisfaction did not deteriorate over time (p < .557). Conclusion: Despite a fair number of DUS-detected recurrences, the overall long-term result, from the patients' point of view was surprisingly favorable. Technically well performed open venous surgery seems to result in a durable long-term outcome.

BACKGROUND: The aim was to clarify the role of incompetent perforators (IPs) in venous leg ulcers. This short-term report focused on safety, patient satisfaction and the fate of IPs after subfascial endoscopic perforator surgery (SEPS), or saphenous surgery alone. METHODS: Patients aged 30-78 years with an open or recently healed venous ulcer, and with an incompetent saphenous vein and IPs, were allocated randomly to saphenous surgery alone, or in combination with SEPS. A control duplex scan was performed 6-9 months after surgery, and clinical follow-up was scheduled after 1 week, 3 and 12 months. A standard questionnaire was completed at each clinical visit. RESULTS: Seventy-five patients were enrolled; 37 had SEPS and 38 had saphenous surgery alone. SEPS prolonged the operation by a median of 15 min (P = 0.003). Duplex imaging revealed significantly more remaining IPs in the no-SEPS group (P < 0.001). Compared with the preoperative scan, significantly more legs were free from IPs in the SEPS group compared with the no-SEPS group (21 of 36 versus 7 of 37 respectively; P < 0.001). There were no other major outcome differences between the groups. CONCLUSION: There was no short-term clinical benefit from adding SEPS to saphenous surgery in patients with varicose ulcers and IPs, although SEPS reduced the number of perforators remaining after 1 year.

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder whose hallmark is bilateral vestibular schwannoma. It displays a pronounced clinical heterogeneity with mild to severe forms. The NF2 tumor suppressor (merlin/schwannomin) has been cloned and extensively analyzed for mutations in patients with different clinical variants of the disease. Correlation between the type of the NF2 gene mutation and the patient phenotype has been suggested to exist. However, several independent studies have shown that a fraction of NF2 patients with various phenotypes have constitutional deletions that partly or entirely remove one copy of the NF2 gene. The purpose of this study was to examine a 7 Mb interval in the vicinity of the NF2 gene in a large series of NF2 patients in order to determine the frequency and extent of deletions. A total of 116 NF2 patients were analyzed using high-resolution array-comparative genomic hybridization (CGH) on an array covering at least 90% of this region of 22q around the NF2 locus. Deletions, which remove one copy of the entire gene or are predicted to truncate the schwannomin protein, were detected in 8 severe, 10 moderate and 6 mild patients. This result does not support the correlation between the type of mutation affecting the NF2 gene and the disease phenotype. This work also demonstrates the general usefulness of the array-CON methodology for rapid and comprehensive detection of small (down to 40 kb) heterozygous and/or homozygous deletions occurring in constitutional or tumor-derived DNA.

Genomic sequencing was combined with searches of databases for identification of active genes on human chromosome 22. A cosmid from 22q13, located in the telomeric vicinity of the PDGFB (platelet-derived growth factor B-chain) gene, was fully sequenced. Using an expressed sequence tag-based approach we characterized human (SYNGR1) and mouse (Syngr1) orthologs of the previously cloned rat synaptogyrin gene (RATSYNGR1). The human SYNGR1 gene reveals three (SYNGR1a, SYNGR1b, SYNGR1c) alternative transcript forms of 4.5, 1.3 and 0.9 kb, respectively. The transcription of SYNGR1 starts from two different promoters, and leads to predicted proteins with different N- and C-terminal ends. The most abundant SYNGR1 a transcript, the 4.5-kb form, which corresponds to RATSYNGR1, is highly expressed in neurons of the central nervous system and at much lower levels in other tissues, as determined by in situ hybridization histochemistry. The levels of SYNGR1b and SYNGR1c transcripts are low and limited to heart, skeletal muscle, ovary and fetal liver. We also characterized two additional members of this novel synaptogyrin gene family in human (SYNGR2 and SYNGR3), and one in mouse (Syngr2). The human SYNGR2 gene transcript of 1.6 kb is expressed at high levels in all tissues, except brain. The 2.2-kb SYNGR3 transcript was detected in brain and placenta only. The human SYNGR2 and SYNGR3 genes were mapped by fluorescence in situ hybridization to 17qtel and 16ptel, respectively. The human SYNGR2 gene has a processed pseudogene localized in 15q11. All predicted synaptogyrin proteins contain four strongly conserved transmembrane domains, which is consistent with the M-shaped topology. The C-terminal polypeptide ends are variable in length, display a low degree of sequence similarity between family members, and are therefore likely to convey the functional specificity of each protein.

Adaptins are important subunits of heterotetrameric complexes called adaptors, which participate in the clathrin-coated, vesicle-mediated endocytosis and intracellular receptor transport. The gene family of adaptins is divided into three classes, alpha, beta, and gamma, with further subdivision into beta- and beta-prime components. Two beta-prime adaptins, the rat AP105a and the human BAM22, have previously been characterized. The BAM22 gene is located on human Chromosome (Chr) 22q12 and can be considered a candidate meningioma tumor suppressor gene. We report here the characterization of the mouse ortholog of the BAM22 gene, and we suggest the name adtb1 for the mouse gene. Like the BAM22 gene, the adtb1 transcript is highly and ubiquitously expressed. We provide 3885-bp cDNA sequence, which entirely covers the open reading frame of the adtb1, capable of encoding a protein of 943 amino acids. The adtb1 protein is highly conserved (>96% identity) when compared with AP105a and BAM22 proteins. We also report the genomic organization of adtb1, which is similar to the BAM22 gene. The adtb1 gene has been assigned to mouse Chr 11, band 11A2, which confirms the synteny between human Chr 22q12 and mouse Chr 11.

Dermatofibrosarcoma protuberans (DP), an infiltrative skin tumour of intermediate malignancy, presents specific features such as reciprocal translocations t(17;22)(q22;q13) and supernumerary ring chromosomes derived from the t(17;22). In this report, the breakpoints from translocations and rings in DP and its juvenile form, giant cell fibroblastoma (GCF), were characterised on the genomic and RNA level. These rearrangements fuse the platelet-derived growth factor B-chain (PDGFB, c-sis proto-oncogene) and the collagen type I alpha 1 (COL1A1) genes. PDGFB has transforming activity and is a potent mitogen for a number of cell types, but its role in oncogenic processes is not fully understood. COL1A1 is a major constituent of the connective tissue matrix. Neither PDGFB nor COL1A1 have so far been implicated in any tumour translocations. These gene fusions delete exon 1 of PDGFB, and release this growth factor from its normal regulation.