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Cardiac Disease
Published in Vincenzo Berghella, Maternal-Fetal Evidence Based Guidelines, 2022
Preethi Pirlamarla, Gregary D. Marhefka
There are a handful of autosomal dominant cardiac conditions, for which the mother would ideally have sought prenatal screening to discuss potential transmission to children. These syndromes include hypertrophic cardiomyopathy, inherited arrhythmias like long QT, Marfan, Noonan, William, Holt-Oram, and DiGeorge (22q11 deletion) [6]. Certain genetic aortopathies are at higher risk for progressive aneurysm formation, dissection and extra-cardiac manifestations, which vary based on etiology. Genetic causes of aortopathy can contribute to intracellular pathology (ACTA2, FLNA, MYLK, PRKG1, MYH11, SKI, SMAD3,4 and TGFβR1,2) or those that affect the extracellular matrix (BGN, COL1A1, COL3A1, 5A1, FBN1, 2, LOX, MFAP5, PLOD1, PRKG1, and TGFβ1,2,3). Other genetic conditions to consider with well-known associated aortopathies are bicuspid aortic valve and Turner's syndrome (XO) [7]. As an ad-hoc member of the cardio-obstetrics team, a geneticist can assist in determining risk profiles.
Glimpses into the molecular pathogenesis of Peyronie’s disease
Published in The Aging Male, 2020
Evert-Jan P. M. ten Dam, Mels F. van Driel, Igle Jan de Jong, Paul M. N. Werker, Ruud A. Bank
Collagen synthesis is a complex process, and many enzymes are involved. Chaperones assist in folding of the procollagen molecules and propeptidases cleave off the propeptides to convert procollagen into collagen. Conversion of proline into 3-hydroxyproline or 4-hydroxyproline is catalyzed by prolyl hydroxylases, conversion of lysine (Lys) into 4-hydroxylysine (Hyl) by lysyl hydroxylases, and cross-linking is initiated by lysyl oxidases [47]. We used a low-density array (Table 2 andFigure 3) to quantify the expression of these enzymes, to clarify whether there were possible aberrations in (pro)collagen processing. An important post-translational modification of collagen is the conversion of triple helical lysine (Lys) into hydroxylysine (Hyl), and the addition of sugars to Hyl, resulting in the glycosylated residues galactosylhydroxylysine (Gal–Hyl) and glucosylgalactosylhydroxylysine (Glc–Gal–Hyl) [26]. It has now been established that the conversion of triple helical Lys into Hyl is catalyzed by lysyl hydroxylase 1 (encoded by PLOD1) and lysyl hydroxylase 3 (encoded by PLOD3), and that the formation of Glc–Gal–Hyl (but not Gal-Hyl) is catalyzed by lysyl hydroxylase 3 [26]. We have observed no differences in mRNA levels of PLOD1 between plaque and control tissue, but there was a major increase in mRNA levels of PLOD3 in plaque tissue. Therefore, an overhydroxylation of Lys in PD tissue is expected, as well as increased levels of Glc–Gal–Hyl. A Lys overhydroxylation and a Hyl overglycosylation have been reported for affected DD tissues [37,40,41].
The role of α-ketoglutarate and the hypoxia sensing pathway in the regulation of pancreatic β-cell function
Published in Islets, 2020
PHDs belong to the iron and αKG-dependent family of dioxygenase that have several primary substrates, including proteins, methylated nucleotides, lipids, and a wide range of small molecules.34 Members of this family include the lysyl, asparaginyl, and proline hydroxylases (Table 1). There are three procollagen-lysine 2‑oxoglutarate 5‑dioxygenases (PLOD1, PLOD2, and PLOD3) that mediate collagen lysine hydroxylation. The hydroxylated lysine residues of collagen have increased stability, which leads to increased tissue stiffness.37 Bones, cartilage, and tendons have a higher percentage of hydroxylated lysine residues in their collagen fibers compared with soft tissues, such as the skin.37 The factor inhibiting HIF-1α (FIH or FIHAN) is an asparagine hydroxylase that acts on the C-terminal activation domain (C-TAD) of HIF-α proteins.38 Asparagine hydroxylation of HIF-α proteins by FIH inhibits the transcriptional activity of HIFs by preventing its binding to the transcriptional co-activators CBP/p300.38
Vascular manifestations and kyphoscoliosis due to a novel mutation of PLOD1 gene
Published in Acta Cardiologica, 2021
Piotr Zieminski, Jessie Risse, Anne Legrand, Virginie Dufrost, Laurence Bal, Nicla Settembre, Sergueï Malikov, Xavier Jeunemaitre, Denis Wahl, Stéphane Zuily
A 42-years-old woman was admitted for a spontaneous dissection of the terminal abdominal aorta (Figure 1, panel A, arrow), associated with an arteriovenous fistula between the false channel of left iliac artery and inferior vena cava (Figure 1, panel B, arrow and panel C, cross). Additionally, the computed tomography (CT) angiogram revealed dysplastic renal arteries (Figure 1, panel C, arrows) and kyphoscoliosis. Past medical history included a symptomatic left vertebral dissection during the peripartum period and a spontaneous right renal artery dissection at 28 years-old. Besides, she suffered from muscular hypotonia with joint hyperlaxity at birth. She walked at 21 months, developed scoliosis during her childhood and had surgery for bilateral shoulders recurrent luxations. Clinically, her skin was thin and translucent, with acrogeria and papyraceous scares on knees. Beighton score was 5/9. This presentation suggested an Ehlers Danlos Syndrome (EDS) with skeletal and vascular involvement. Thus, she received exclusively medical treatment with strict bed rest, blood pressure control and β-blocker (celiprolol). Three years later, there was no new vascular event and CT angiogram did not reveal any aneurysmal evolution. Genetic testing identified a compound heterozygosity in PLOD1 gene, confirming a kyphoscoliotic EDS (kEDS): duplication of exons 10 to 16, found in 20% of kEDS patients and a novel nonsense variant in exon 18 p.(Gln636Ter). This observation emphasises the importance of identifying kEDS in case of vascular abnormalities (dissection, aneurysm) associated with kyphoscoliosis. Vascular prognosis and soft tissue fragility are as severe as in the vascular EDS related to COL3A1 gene mutations, requiring non-invasive treatment.