Ulrich Mahlknecht

Sirtuin 7 (SIRT7) is a member of the sirtuin family of protein deacetylases and is, therefore, a derivative of yeast Silent information regulator 2 (SIR2). SIR2 and its mammalian orthologs play an important role in epigenetic gene silencing, DNA recombination, cellular differentiation and metabolism, and the regulation of aging. In contrast to most sirtuins, SIRT7 does not exert characteristic NAD+-dependent deacetylase activity. We have isolated and characterized the human Sirt7 genomic sequence, which spans a region of 6.2 kb and which has one single genomic locus. Determination of the exon/intron splice junctions found the full-length SIRT7 protein to consist of 10 exons ranging in size from 71 bp (exon 4) to 237 bp (exon 7). The human Sirt7 open reading frame encodes a 400-aa protein with a predictive molecular weight of 44.9 kDa and an isoelectric point of 9.80. Characterization of the 5' flanking genomic region, which precedes the Sirt7 open reading frame, revealed a TATA- and CCAAT-box less promoter that lacks CpG islands. A number of AML-1 and GATA-x transcription factor binding sites were found, which remain to be further evaluated experimentally. Fluorescence in situ hybridization analysis localized the human Sirt7 gene to chromosome 17q25.3; a region which is frequently affected by chromosomal alterations in acute leukemias and lymphomas. Human SIRT7 appears to be most predominantly expressed in the blood and in CD33+ myeloid bone marrow precursor cells, while the lowest levels are found in the ovaries and skeletal muscle. Functional characteristics of SIRT7 are essentially unknown at present and remain to be further elucidated.

Angesichts der zunehmend alternden Bevölkerung in der westlichen Welt, stetig steigende Sozialausgaben und wachsende Kosten für Pflege und Gesundheit einschließlich der Behandlung unerwünschter Medikamentennebenwirkungen geraten öffentliche Finanzträger und die Krankenkassen zunehmend unter Druck. Arzneimittel wurden bislang auf der Grundlage statistisch ermittelter Durchschnittswerte, die an homogenen Personengruppen ermittelt wurden, aufgrund empirischer Erfahrungswerte oder willkürlicher Entscheidungen verordnet, in der Erwartung, dass der Großteil der Behandelten davon profitieren wird. Dabei wurde bisher auf potenzielle Diskrepanzen hinsichtlich der therapeutischen Wirksamkeit und Verträglichkeit wenig Rücksicht genommen. Kriterien dieser Art haben sicherlich dazu beigetragen, dass die öffentliche Akzeptanz der relativ neuen Wissenschaftszweige der Pharmakogenetik und Pharmakogenomik sehr groß ist und diesen einen wichtigen gesundheitspolitischen und gesundheitsökonomischen Stellenwert verleihen: Denn diese versprechen eine individualisierte Behandlung, die sicherer und wirksamer sein soll als zuvor bei einer gleichzeitig zu erwartenden langfristigen Kostensenkung. Pharmakogenetik und Pharmakogenomik untersuchen die funktionellen Auswirkungen genetischer Variabilität auf Wirkung und Toxizität von Arzneimitteln zwischen einzelnen Populationen bzw. Individuen und haben letztlich durch die Entwicklung individuell maßgeschneiderter Medikamente eine Verbesserung der Arzneimittelsicherheit zum Ziel. Trotz des außerordentlichen Nutzens, welcher von diesen neuen Entwicklungen zu erwarten ist, gehen diese doch mit einer Reihe moralischer, gesellschaftlicher und rechtlicher Bedenken einher. Diese verlangen dringend nach einem strengen internationalen Regelwerk, um einem Missbrauch und Diskriminierungen jeder Art rechtzeitig vorzubeugen.

Sirtuin 6 (SIRT6) is a member of the sirtuin deacetylases (sirtuins), which are derivatives of the yeast Silent information regulator 2 (Sir2) protein. SIR2 and its mammalian derivatives play a central role in epigenetic gene silencing, recombination, metabolism, cell differentiation and in the regulation of aging. In contrast to most sirtuins, SIRT6 lacks NAD+-dependent protein deacetylase activity. We have isolated and characterized the human Sirt6 genomic sequence, which spans a region of 8,427 bp and which has one single genomic locus. Determination of the exon-intron splice junctions found the full-length SIRT6 protein to consist of 8 exons ranging in size from 60 bp (exon 4) to 838 bp (exon 8). The human Sirt6 open reading frame encodes a 355-aa protein with a predictive molecular weight of 39.1 kDa and an isoelectric point of 9.12. Characterization of the 5' flanking genomic region, which precedes the Sirt6 open reading frame, revealed a TATA- and CCAAT-box less promoter with an approximately 300-bp long CpG island. A number of AML-1 and GATA-x transcription factor binding sites were found which remain to be further evaluated experimentally. Fluorescence in situ hybridization analysis localized the human Sirt6 gene to chromosome 19p13.3; a region which is frequently affected by chromosomal alterations in acute leukemia. Human SIRT6 appears to be most predominantly expressed in bone cells and in the ovaries while, in the bone marrow, it is practically absent. The functional characteristics of SIRT6 are essentially unknown at present and remain to be elucidated.

Sirtuin 5 (SIRT5) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase and belongs to the Silent information regulator 2 (Sir2) family of sirtuin histone deacetylases (HDACs), which play a central role in epigenetic gene silencing, DNA repair and recombination, cell-cycle, microtubule organization, and in the regulation of aging. We have isolated and characterized the human SIRT5 genomic sequence, which spans a region of 28,182 bp and which has one single genomic locus. Human SIRT5 consists of eight exons and is found in two isoforms, which encode a 310 aa and a 299 aa protein, respectively. Human SIRT5 is most predominantly expressed in heart muscle cells and in lymphoblasts. Fluorescence in situ hybridization analysis localized the human SIRT5 gene to chromosome 6p23.

Sir, We report the case of a 60-yr-old patient who suffered from chronic lymphocytic leukaemia (CLL) with concomitant relapsing polychondritis. Polychondritic exacerbations were regularly observed with CLL progression and included bilateral painful swellings of the external ear cartilage and of the trachea, disseminated inflammatory polyarthritis, ocular inflammation and a palatal ulceration (Fig. 1). All manifestations of polychondritis and CLL responded well to chlorambucil/prednisone initially, and to cyclophosphamide during later stages of the disease, while the response to methotrexate was poor and treatment with bendamustin was complicated by tumour lysis syndrome and subsequent acute renal failure. Treatment with cyclophosphamide repeatedly induced remissions for both diseases, but was regularly accompanied by serious infectious complications. Relapsing polychondritis is rare and is generally diagnosed clinically if the patient develops at least three of the following signs: bilateral chondritis of the external ears, inflammatory polyarthritis, ocular inflammation, nasal chondritis, vestibular/auditory malfunction and respiratory tract chondritis. Notably, its 5-yr mortality may be as high as 30%, due to collapse of laryngeal and tracheal cartilaginous supporting structures, or cardiovascular involvement. Mild cases may respond to NSAIDs. More severe cases are usually treated with prednisone and may require additional immunosuppressive agents, e.g. cyclophosphamide [1].