Summary
Focal dermal hypoplasia (FDH, Goltz syndrome, MIM #305600) constitutes a rare multisystem genetic disorder of the skin, skeleton, teeth and eyes with considerable variation in the clinical ...features. FDH is transmitted as an X‐linked dominant trait and is caused by mutations in PORCN. In male children, hemizygous PORCN mutations are lethal in utero. Around 300 cases have been reported in the literature to date. About 10% of them are male patients presenting with either Klinefelter syndrome (karyotype 47, XXY) or mosaicism of a postzygotic mutation. Here we describe four cases of women with typical features of FDH, in whom a PORCN mutation was found in DNA from affected cutaneous tissue but not in DNA from peripheral blood. This study suggests that mosaicism caused by a postzygotic mutation occurs more often than assumed to date in female patients with FDH. A negative analysis performed on peripheral blood DNA does not exclude the diagnosis of FDH and it is therefore of practical importance to analyse DNA from the affected skin in order to identify low‐level mosaicism and thus to improve diagnostic precision. In total, we found two missense variants, one novel indel and one novel splice‐site variant. Individuals harbouring postzygotic mosaicism run a risk of transmitting the disorder to their daughters, because the maternal mosaic could also affect the gonads.
What's already known about this topic?
Mutations in PORCN cause focal dermal hypoplasia (FDH).
In male children, hemizygous PORCN mutations are lethal in utero.
To date, only around 300 patients with mutations in PORCN have been reported.
What does this study add?
In four women affected by FDH, PORCN mutations were found to be present in affected cutaneous tissue but not in peripheral blood.
Negative mutation analysis of blood samples does not exclude the diagnosis of FDH, as a mosaic constellation due to postzygotic mutations has been repeatedly observed in female patients with FDH as shown in this study.
Linked Comment: Traupe. Br J Dermatol 2019; 180:461–462.
Plain language summary available online
Mosaicism in women with focal dermal hypoplasia Heinz, L.; Bourrat, E.; Vabres, P. ...
British journal of dermatology (1951),
March 2019, 2019-03-00, 20190301, Letnik:
180, Številka:
3
Journal Article
Recenzirano
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Summary
This report from Germany and France describes four women with focal dermal hypoplasia (FDH), a genetic condition affecting the skin, skeleton, teeth and eyes. FDH is caused by a mutant ...(abnormal) gene called PORCN, found on the X chromosome. Male embryos with the mutant gene do not usually survive. Females are more complicated. Firstly, they have two X chromosomes, but for FDH to show up it only needs the mutant gene to be present on one of them. Secondly, soon after conception one of the two X chromosomes in each cell of the embryo is randomly deactivated. Cell lines (daughter cells) from cells where the normal X chromosome remains active develop normally; cell lines where the abnormal X chromosome remains active develop abnormally owing to the mutant gene. This phenomenon, where cell lines in an individual represent different genetic populations, is called mosaicism (and, incidentally, explains why tortoiseshell cats are always female). The FDH mutation also frequently happens spontaneously after fertilisation, in the earliest stages of development, but before X chromosome deactivation. The main message from this report is that one cannot exclude FDH simply by using standard genetic tests on blood alone. In affected women, in whom the clinical signs may be subtle and a blood test negative, because of mosaicism the abnormal gene may still be found in those skin cells where the X chromosome carrying it remains active. Importantly, the ovaries may also contain such cells, in which case the condition could be passed on to children.
Linked Article: Heinz et al. Br J Dermatol 2019; 180:657–661
Mannitol, an acyclic six-carbon polyol, is one of the most abundant sugar alcohols occurring in nature. In the button mushroom, Agaricus bisporus, it is synthesized from fructose by the enzyme ...mannitol 2-dehydrogenase (MtDH; EC 1.1.1.138) using NADPH as a cofactor. Mannitol serves as the main storage carbon (up to 50% of the fruit body dry weight) and plays a critical role in growth, fruit body development, osmoregulation, and salt tolerance. Furthermore, mannitol dehydrogenases are being evaluated for commercial mannitol production as alternatives to the less efficient chemical reduction of fructose. Given the importance of mannitol metabolism and mannitol dehydrogenases, MtDH was cloned into the pET28 expression system and overexpressed in Escherichia coli. Kinetic and physicochemical properties of the recombinant enzyme are indistinguishable from the natural enzyme. The crystal structure of its binary complex with NADP was solved at 1.5-Å resolution and refined to an R value of 19.3%. It shows MtDH to be a tetramer and a member of the short chain dehydrogenase/reductase family of enzymes. The catalytic residues forming the so-called catalytic triad can be assigned to Ser149, Tyr169, and Lys173.
Background:
Early diagnostic evaluation of TIA is warranted, since rapid initialization of secondary prophylaxis can reduce the risk of stroke after TIA significantly. The TIA clinic should provide ...diagnostic evaluation, stratification of stroke risk, and decision-making within less than one day.
Methods:
The TIA clinic provides a stroke work-up with cerebral MRI (DWI, FLAIR, FFE, TOF angio), duplexsonography of extracranial arteries, TCD-PFO-screening, ECG and blood tests. According to ABCD_2 Score, Essen Stroke Risk Score (ESRS), and ancle-brachial-index (ABI), secondary stroke prophylaxis is initialized or the patient is referred to the stroke unit.
Results:
Thirty patients were seen from February to March, 2009. Among them, there were 7 TIAs (23,3%), 3 strokes (10%), 6 migraines with aura (20%), 1 transient global amnesia (3,3%), 1 Menière's disease (3,3%), 1 BPPV (3,3%), 2 suspected focal seizures (6,6%), and 8 other diagnoses (26,7%). Median time from symptom onset to admission was 48h (range 1h to 6 weeks), median duration of symptoms was 30min (range 1min to 6 weeks). Mean ABCD_2 score was 2,4±1,3, mean ESRS 1,3±1,4, mean ABI 1,0±0,1. Twenty nine patients (97%) were sent home the same day. One patient with symptomatic ACI stenosis (ABCD_2 score 5, ESRS 3) was referred to the stroke unit and received urgent carotid revascularization. TIA patients received ASS 300mg immediately. Stroke secondary prophylaxis, and in some cases additional diagnostic work-up was recommended to the GP according to the individual cardiovascular risk profile.
Conclusion:
An urgent stroke work-up can confirm the diagnosis of TIA within one day on an ambulatory basis. Many of the referred patients do not have a TIA, but another transient neurological attack. TIA patients at high risk for acute stroke can be identified by stroke risk scores and admitted to the stroke unit. Most patients are discharged home the same day.
Mannitol dehydrogenase (MtDH) is a key enzyme controlling the reductive synthesis of mannitol from fructose in the common mushroom Agaricus bisporus. A better understanding of the control of mannitol ...metabolism can be obtained by studying the structure of this enzyme. Here, the purification and crystallization of recombinant MtDH are reported. Crystals generally belonged to the space group C2, with unit‐cell parameters a = 227, b = 125, c = 133 Å, β = 118°, and diffracted to at least 1.8 Å resolution, although a tantalum derivative belonged to the space group P21 and diffracted to the lower resolution of 2.9 Å.
A new angucyclinone antibiotic, frigocyclinone, was isolated from Streptomyces griseus strain NTK 97, consisting of a tetrangomycin moiety attached through a C-glycosidic linkage with the ...aminodeoxysugar ossamine. Frigocyclinone showed antibacterial activities against Gram-positive bacteria.
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