Abstract:Obstructive sleep apnoea (OSA) is a common disorder characterized by repetitive episodes of nocturnal breathing cessation due to upper airway collapse. OSA causes severe symptoms, such as excessive daytime somnolence, and is associated with a significant cardiovascular morbidity and mortality. Different treatment options are now available for an effective management of this disease. After more than three decades from its first use, continuous positive airway pressure (CPAP) is still recognized as the gold standard treatment. Nasal CPAP (nCPAP) is highly effective in controlling symptoms, improving quality of life and reducing the clinical sequelae of sleep apnoea. Other positive airway pressure modalities are available for patients intolerant to CPAP or requiring high levels of positive pressure. Mandibular advancement devices, particularly if custom made, are effective in mild to moderate OSA and provide a viable alternative for patients intolerant to CPAP therapy. The role of surgery remains controversial. Uvulopalatopharyngoplasty is a well established procedure and can be considered when treatment with CPAP has failed, whereas maxillarmandibular surgery can be suggested to patients with a craniofacial malformation. A number of minimally invasive procedures to treat snoring are currently under evaluation. Weight loss improves symptoms and morbidity in all patients with obesity and bariatric surgery is an option in severe obesity. A multidisciplinary approach is necessary for an accurate management of the disease.

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Hereditary predisposition to lipomas is observed in familial multiple lipomatosis (OMIM 151900) and benign cervical lipomatosis (OMIM 151800) and can also be associated with mutations in the MEN1 and PTEN genes (OMIM 131100 and 153480, respectively). In addition, a recent report indicates that a few patients with hereditary retinoblastoma also have lipomas. Here we report on an extended family segregating a splice site mutation in the RB1 gene. Almost all adult carriers of this mutation had multiple lipomas while penetrance for retinoblastoma was incomplete. In an unrelated pedigree, which was reported previously, the identical mutation was only associated with low-penetrance retinoblastoma but not lipomas. Our data indicate that lipoma predisposition in hereditary retinoblastoma is not associated with specific RB1 gene mutations but is influenced by modifying factors linked to this gene. European Journal of Human Genetics (2001) 9, 690 ± 694.

the scalp-ear-nipple (seN) syndrome is an autosomal-dominant disorder characterized by cutis aplasia of the scalp and malformations of breast, external ears, digits, and nails. Genetic analyses have shown that the disease is caused by missense mutations of the KCTD1 protein, although the functional/ structural basis of seN insurgence is hitherto unknown. With the aim of unravelling the molecular basis of the SEN syndrome associated with KCTD1 mutations we here expressed and characterized several disease causing mutants. A preliminary dissection of the protein provides insights into the role that individual domains play in KCTD1 stability. The characterization of SEN-causing mutants indicates that, although the mutation sites are located in distant regions of the BtB domain or of the pre-BtB region, all of them are unable to interact with the transcription factor AP-2α, a well-known KCTD1 biological partner. Notably, all mutations, including the one located in the pre-BTB region, produce a significant destabilization of the protein. The structural role of the pre-BTB region in KCTD1 and other proteins of the family is corroborated by its sequence conservation in orthologs and paralogs. Interestingly, seNcausing mutations also favor the tendency of KCTD1 to adopt structural states that are characterized by the ability to bind the β-amyloid fluorescent dye thioflavin T. The formation of aggregation-prone species may have important implications for the disease etiology. Collectively, these findings provide an intriguing picture of the functional and structural alterations induced by KCTD1 mutations that ultimately lead to disease. Members of the KCTD (Potassium Channel Tetramerization Domain) family represent an emerging class of proteins that play a key role in fundamental physio-pathological processes 1-16. Investigations carried out in the last decade have highlighted analogies and differences among different members from both the structural and the functional points of view. Although the biochemical activities of these proteins are still somehow obscure, the biological characterizations of KCTDs have disclosed their crucial roles in highly diversified processes such as protein ubiquitination and degradation 13,15-17 , binding and modulation of the GABA B receptor 18-22 , autophagy 23 , adipogenesis 24 (Pirone et al. unpublished results), sleep homeostasis 25,26 and metabolic homeostasis 27. Not surprisingly, they are also involved in the insurgence of severe pathological states that include epilepsy, cancer, obesity, and skin diseases. A number of these pathologies are generated by mutations of KCTD proteins whose structural interpretations have been scarcely investigated 28,29. In particular, the allelic deletion of human KCTD11 at chromosomal location 17p13.2 has been found in medulloblastoma 30,31 whereas single nucleotide polymorphisms (SNPs) of KCTD10 (i5642G > C and V206VT > C) are associated with altered concentrations of HDL cholesterol in subjects with high levels of carbohydrate intake 9,32. It has been...