Sixteen novel mutations in PNPLA1 in patients with autosomal recessive congenital ichthyosis reveal the importance of an extended patatin domain in PNPLA1 that is essential for proper human skin barrier function.

BACKGROUND: Autosomal recessive congenital ichthyosis (ARCI) is a genetically heterogeneous group of rare Mendelian skin disorders characterized by cornification and differentiation defects of keratinocytes. Mutations in nine genes including PNPLA1 are known to cause nonsyndromic forms of ARCI. To date, only 10 distinct pathogenic mutations in PNPLA1 have been reported. OBJECTIVES: To identify new causative PNPLA1 mutations. METHODS: We screened genetically unresolved cases, including our ARCI collection, comprising more than 700 families. Screening for mutations was performed either by direct Sanger sequencing or in combination with a multigene panel, followed by sequence and mutation analysis. RESULTS: Here we report on 16 novel mutations present in patients from 17 families. While all previously reported mutations and most of our novel mutations are located within the core patatin domain, we report five novel PNPLA1 mutations that are downstream of this domain. Thus, as recently described for PNPLA2, we hypothesize that a region larger than the core domain is required for full enzymatic activity of PNPLA1 in human skin barrier formation. CONCLUSIONS: We estimate the frequency of PNPLA1 mutations among patients with ARCI to be around 3%. Most of our patients were born as collodion babies and showed a relatively mild ichthyosis phenotype. In four unrelated patients we observed a cyclic scaling course, which seems to be a potential phenotypic variation in a small percentage of patients with PNPLA1 mutations. The variability of the clinical manifestations and the lack of typical clinical features are specific for patients with PNPLA1 mutations, and emphasize the importance of DNA sequencing for differential diagnosis of ARCIs.

[Erythematosquamous dermatoses in adolescence]. / Erythematosquamöse Erkrankungen in der Adoleszenz.

Erythematosquamous dermatoses in adolescents comprise a wide range of differential diagnoses. Age-typical variations of the clinical manifestation, the need to differentiate common conditions from rare diseases as well as the tremendous psychosocial impact which the patients perceive especially in this vulnerable period of life can become major challenges for pediatric dermatologists. This article summarizes key features of common erythematosquamous dermatoses and less frequent skin diseases occurring during adolescence.

[Harlequin ichthyosis--medical and psychosocial challenges]. / Ichthyosis congenita gravis--eine medizinische und psychosoziale Herausforderung.

Harlequin ichthyosis is the most severe congenital keratinizing disorder. It is caused by mutations in the ABCA12 gene leading to defective lipid transport. The infants are born with ectropion, eclabium and fissured plate-like skin. Today these infants can survive with neonatal intensive care and retinoid therapy and need long-term interdisciplinary treatment in order to improve quality of life. However, the outcome in our case is impaired by severe psychomotor developmental delay, which has not yet been associated with Harlequin Ichthyosis.

Work and contraction curves of atrial muscle preparations during anoxia and reoxygenation influenced by cardio-tonic and cardio-depressive drugs.

Auxotonic work/beat and contraction curves were recorded from left guinea pig atria stimulated with 0.5 Hz at 5 mN preload in K.H.-solution + 15 mmol/l glucose, 95% O2 or N2 + 5% CO2, 30 degrees C. Eight common parameters of the contraction curve were calculated simultaneously in a computerized system as reported previously (Englert, R. et al., N.-Arch. of Pharmacol., 337, Suppl. R. 60, 1988). By increased anaerobic glycolysis anoxia reduced contractile activity which after 30 min reached a plateau of approximately 50% of the initial aerobic value during approximately 2 hours. At reoxygenation the contraction force increased with a first peak overshooting 50% of the initial aerobic value after 5-10 min, to decline during the following 10-15 min to a plateau slightly below the initial aerobic value. Several parameters exhibited characteristic changes during anoxia and reoxygenation: during the first minutes of reoxygenation in the ascension of the first peak the 'time to peak force', the 'relaxation time' and the 'area under the contraction curve', especially the part below the relaxation, were strongly but only transiently increased. Positive and negative inotropic agents influencing cytosolic free Ca2+ in different ways applied 15 minutes before reoxygenation indicated that the observed overshooting peak of force and the prolongation of contracation duration after reoxygenation were presumably due to transiently disturbed intracellular Ca2+ redistribution in sarcoplasmic reticulum and mitochondria during the restitution of high energy phosphates.

Effects of the divalent cation ionophore ionomycin on the performance of isolated guinea-pig atria.

In isolated electrically driven left and in spontaneously beating right guinea-pig atria, the calcium ionophore ionomycin produced a concentration-dependent positive inotropic and chronotropic effect with a threshold near 10(-7) mol/l and a pD2 of 6.31 +/- 0.09 and 5.94 +/- 0.07, respectively. At low [Ca2+]o (0.5 mmol/l), the positive inotropic effect of ionomycin (3 X 10(-6) mol/l) was strongly attenuated by ryanodine and nifedipine, and slightly attenuated by pindolol and mepyramine; atropine had no effect. The positive chronotropic effect of ionomycin was slightly reduced by cimetidine or pindolol, whereas atropine, nifedipine, and ryanodine showed no inhibitory activity. The oxygen consumption of resting left atria was significantly enhanced by addition of ionomycin. It is concluded that the action of ionomycin involves at least the following mechanisms: I) release of Ca2+ from sarcoplasmic reticulum, II) influx of Ca2+ from the extracellular space, and, having little significance, III) release of catecholamines and histamine from sympathetic nerve endings and tissue mast cells. However, additional mechanisms of action of ionomycin cannot be excluded.

Some problems of cardiac energetics.

Special problems of the aerobic metabolism in the cardiac muscle cell as an energy producing and energy consuming system are discussed and demonstrated with some experimental results using superfused resting and working guinea-pig atria as an energetic model: 1. Influence on resting O2 uptake: a) Free fatty acids (FFA) increase the O2 uptake rate to approximately 20% compared with glucose oxidation. This can be explained as a compensating effect due to the 9.7% lower combustion value for 1 mol O2 of C16-FFA and the 10.7% lower P/O-ratio related to glucose oxidation. b) K+-depolarization increases the O2 uptake b.1. between 15 and 65 mmol/l KCl from 110 to 200% without activation of the actomyosin system. This effect is Ca++ dependent and is not observed in Ca++ free solution and can be inhibited completely by nifedipine. The enhanced O2 uptake rate due to K+-depolarization is not connected with an improved state of the energy quotient (ATP/ADP+AMP) indicating a lowering of the energy coupling. b.2. between 100 and 250 mmol/l KCl from 220 to approximately 350%, not influenced by nifedipine and connected with activation of the actomyosin system at low Na+ and/or high external Ca++ (contracture). 2. Stretching of resting atria up to 10 mN tension does not increase the O2 uptake rate. The 'Feng' effect could not be confirmed. 3. a) The 'Frank-Starling' effect can be observed between 2.5 and 10 mN preload with increase of contractile work/beat connected with an enhancement of O2 uptake rate to a lower percentage. At the maximum of the 'Frank-Starling' effect the highest efficiency of contractile work can be observed. With increasing beat rate this maximum is shifted to a lower preload. b) The auxotonic contractile work measured by a calibrated spring blade allows the calculation of the 'internal work' and the 'external contractile work'/beat in mm X mN. The total energy of the activated actomyosin system (total work) is stored by the displacement of the spring blade due to the constant of the spring blade, the preload (tension) and the afterload (force). The 'internal work' will be transformed into ATP dependent heat and force equal to the preload tension. The same ATP dependent energy from O2 uptake is transformed at the same beat rate and the same preload a) with the isometric type of auxotonic contraction into high force and very low internal and low external work.(ABSTRACT TRUNCATED AT 400 WORDS)

[The effect of AR-L 115 BS on the function and oxygen consumption of isolated guinea pig atria as compared to g-strophanthin and theophylline]. / Zur Wirkung von AR-L 115 BS auf Funktion und Sauerstoffverbrauch isolierter Meerschweinchenherzvorhöfe im Vergleich zu g-Strophanthin und Theophyllin.

Dose-response curves with ouabain, theophylline and 2-[(2-methoxy-4- methylsulfinyl)phenyl] -1H-imidazo[4,5-b]pyridine (AR-L 115 BS) were obtained from electrically driven isolated left guinea pig atria (at 35 degrees C and 3 Hz, 0.5 ms and 0.4--0.6 mA 10% above threshold) measuring the auxotonic contraction work beat. The dose-response curve of the inotropy and frequency was very similar in shape to that of theophylline as far as intensity of inotropy and the range of dosage is concerned, but AR-L 115 BS is 10 times as active. The maximum of the increase of frequency was less under AR-L 115 BS than under theophylline. Also the toxicities of the two substances are very similar with a concomitant decline of inotropism. Both substances are clearly distinct from ouabain. As to the economic effect, however, AR-L 115 BS shows, in submaximally effective concentrations, similarity to the economic type of ouabain whereas, at the maximum of contractile activity, the efficiency is lowered as was observed with theophylline. In the "anoxia test" the anoxic tolerance was shortened by AR-L 115 BS similar to theophylline when the anoxic contractile activity was stimulated below the maximum level in contrast to the prolongation due to ouabain.