Ogden syndrome | |
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Other names | Premature aging appearance-developmental delay-cardiac arrhythmia syndrome, N-terminal acetyltransferase deficiency |
Ogden syndrome, also known as N-terminal acetyltransferase deficiency (NATD), [1] is an X-linked disorder of infancy comprising a distinct combination of distinctive craniofacial features producing an aged appearance, growth failure, hypotonia, global developmental delays, cryptorchidism, and spontaneous cardiac arrhythmias. The first family was identified in Ogden, Utah, with five affected boys in two generations of family members. A mutation was identified as a c.109T>C (p.Ser37Pro) variant in NAA10, a gene encoding the catalytic subunit of the major human N-terminal acetyltransferase enzyme system (NatA). This same mutation was identified in a second unrelated family, with three affected boys in two generations. This severe genetic disorder has provisionally been named Ogden syndrome, as this is the city where the first affected family resides.
This is an X-linked condition affecting males more than females and is characterized by postnatal growth failure with developmental delays and dysmorphic features characterized by wrinkled forehead, anterior and posterior fontanels, prominent eyes, large down-slanting palpebral fissures, thickened or hooded eyelids, large ears, flared nares, hypoplastic alae nasi, short columella, protruding upper lip, and microretrognathia. There is also delayed closing of fontanelle, and the boys also have broad great toes. Skin is characterized by redundancy or laxity with minimal subcutaneous fat, cutaneous capillary malformations, and very fine hair and eyebrows. Death resulted from cardiogenic shock following arrhythmia, which was noted in all affected individuals. The boys had heart rhythm abnormalities and craniofacial abnormalities, which accounted for their similar appearance. The boys were never able to sit up on their own, and none learned how to talk. [2] They all had a characteristically aged appearance, earning them the family nickname of "little old men." [2] Several of the boys had structural anomalies of their hearts including ventricular septal defect, atrial septal defect, and pulmonary artery stenosis. Events recorded on electrocardiogram before death included torsades de pointes, premature ventricular contraction (PVC), premature atrial contraction (PAC), supraventricular tachycardia (SVtach), and ventricular tachycardia (Vtach). Most of the children had inguinal hernias, and the majority had, at least, unilateral cryptorchidism. All had neonatal hypotonia progressing to hypertonia, and cerebral atrophy on MRI; several, but not all, had neurogenic scoliosis. Death occurred prior to two years in all cases and prior to one year in the majority. There are extensive clinical details for each child reported in the original publication
Ogden syndrome is a lethal X-linked recessive condition. Because the affected gene is on the X-chromosome, it affects males far more severely due to the fact that males only carry one copy of the X chromosome so the mutation is in every cell but females carry two and therefore some cells may use the non mutated copy and others use the mutated copy. It was the first reported human genetic disorder linked with a mutation in an N-terminal acetyltransferase (NAT) gene. [3] The original Ogden family males have the Ser37Pro (S37P) mutation in the gene encoding NAA10, the catalytic subunit of NatA, the major human enzyme heterodimer involved in the post-translational acetylation of proteins. The S37P mutation swaps one amino acid for another, a serine for a proline, in just one part at the end of the resulting NatA protein subunit. [3] Other mutations have since been discovered in very small number of cases worldwide with the most prevalent being Arg83Cys mutation. Mutations to this gene changes the structure of the protein, which makes it less effective at N-terminal acetylation than the normal protein, causing a multitude of effects for the baby, as N-terminal acetylation is one of the most common protein modifications in humans, occurring on approximately 80% of all human proteins. [2] [4]
Whole exome sequencing is the definitive diagnostic method used to confirm OS.
Halena Black had her first son, Kenny Rae, in 1979. Being that he was her first born child, Black did not notice that something was wrong. Kenny Rae Black passed in 1980, right before his first birthday and was the first known infant to die from Ogden syndrome. [5] However, it did not end there. Halena Black continued to have children and in 1987 she had her next boy, Hyrum. From the start, Black noticed that Hyrum had the same characteristics as Kenny Rae but thought it was due to the fact that they were brothers. Like Kenny Rae, Hyrum passed before his first birthday. It was only until Black's daughters began having children of their own that she realized something was not right. The sons born to Black's daughters looked identical to her own sons and that was when Halena sought medical help. [5]
Answers came thirty years after Kenny Rae's death. Ogden syndrome was discovered in 2011 by a team of researchers led by Gholson J. Lyon, consisting of: Alan F. Rope, Kai Wang, Rune Evjenth, Jinchuan Xing, Jennifer J. Johnston, Jeffrey J. Swensen, W. Evan Johnson, Barry Moore, Chad D. Huff, Lynne M. Bird, John C. Carey, John M. Opitz, Cathy A. Stevens, Tao Jiang, Christa Schank, Heidi Deborah Fain, Reid J. Robison, and 10 others. Just before Lyon was about to publish his findings, another team researching a family living mainly in California contacted him. The newly found family had also lost three infant boys all with similar characteristics. This new family shared the same rare mutation as the Black family. The existence of another family made this mutation a syndrome, and not something isolated. [2]
Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-N-acetyllysine. DNA is wrapped around histones, and, by transferring an acetyl group to the histones, genes can be turned on and off. In general, histone acetylation increases gene expression.
Romano–Ward syndrome is the most common form of congenital Long QT syndrome (LQTS), a genetic heart condition that affects the electrical properties of heart muscle cells. Those affected are at risk of abnormal heart rhythms which can lead to fainting, seizures, or sudden death. Romano–Ward syndrome can be distinguished clinically from other forms of inherited LQTS as it affects only the electrical properties of the heart, while other forms of LQTS can also affect other parts of the body.
Histone H4 is one of the five main histone proteins involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N-terminal tail, H4 is involved with the structure of the nucleosome of the 'beads on a string' organization. Histone proteins are highly post-translationally modified. Covalently bonded modifications include acetylation and methylation of the N-terminal tails. These modifications may alter expression of genes located on DNA associated with its parent histone octamer. Histone H4 is an important protein in the structure and function of chromatin, where its sequence variants and variable modification states are thought to play a role in the dynamic and long term regulation of genes.
A coactivator is a type of transcriptional coregulator that binds to an activator to increase the rate of transcription of a gene or set of genes. The activator contains a DNA binding domain that binds either to a DNA promoter site or a specific DNA regulatory sequence called an enhancer. Binding of the activator-coactivator complex increases the speed of transcription by recruiting general transcription machinery to the promoter, therefore increasing gene expression. The use of activators and coactivators allows for highly specific expression of certain genes depending on cell type and developmental stage.
CREB-binding protein, also known as CREBBP or CBP or KAT3A, is a coactivator encoded by the CREBBP gene in humans, located on chromosome 16p13.3. CBP has intrinsic acetyltransferase functions; it is able to add acetyl groups to both transcription factors as well as histone lysines, the latter of which has been shown to alter chromatin structure making genes more accessible for transcription. This relatively unique acetyltransferase activity is also seen in another transcription enzyme, EP300 (p300). Together, they are known as the p300-CBP coactivator family and are known to associate with more than 16,000 genes in humans; however, while these proteins share many structural features, emerging evidence suggests that these two co-activators may promote transcription of genes with different biological functions.
Trifunctional enzyme subunit beta, mitochondrial (TP-beta) also known as 3-ketoacyl-CoA thiolase, acetyl-CoA acyltransferase, or beta-ketothiolase is an enzyme that in humans is encoded by the HADHB gene.
Potassium voltage-gated channel subfamily E member 2 (KCNE2), also known as MinK-related peptide 1 (MiRP1), is a protein that in humans is encoded by the KCNE2 gene on chromosome 21. MiRP1 is a voltage-gated potassium channel accessory subunit associated with Long QT syndrome. It is ubiquitously expressed in many tissues and cell types. Because of this and its ability to regulate multiple different ion channels, KCNE2 exerts considerable influence on a number of cell types and tissues. Human KCNE2 is a member of the five-strong family of human KCNE genes. KCNE proteins contain a single membrane-spanning region, extracellular N-terminal and intracellular C-terminal. KCNE proteins have been widely studied for their roles in the heart and in genetic predisposition to inherited cardiac arrhythmias. The KCNE2 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease. More recently, roles for KCNE proteins in a variety of non-cardiac tissues have also been explored.
Young–Simpson syndrome (YSS) is a rare congenital disorder with symptoms including hypothyroidism, heart defects, facial dysmorphism, cryptorchidism in males, hypotonia, intellectual disability, and postnatal growth retardation.
In enzymology, an alpha-tubulin N-acetyltransferase is an enzyme which is encoded by the ATAT1 gene.
N-alpha-acetyltransferase 10 (NAA10) also known as NatA catalytic subunit Naa10 and arrest-defective protein 1 homolog A (ARD1A) is an enzyme subunit that in humans is encoded NAA10 gene. Together with its auxiliary subunit Naa15, Naa10 constitutes the NatA complex that specifically catalyzes the transfer of an acetyl group from acetyl-CoA to the N-terminal primary amino group of certain proteins. In higher eukaryotes, 5 other N-acetyltransferase (NAT) complexes, NatB-NatF, have been described that differ both in substrate specificity and subunit composition.
K(lysine) acetyltransferase 6A (KAT6A), is an enzyme that, in humans, is encoded by the KAT6A gene. This gene is located on human chromosome 8, band 8p11.21.
N-alpha-acetyltransferase 15, NatA auxiliary subunit also known as gastric cancer antigen Ga19 (GA19), NMDA receptor-regulated protein 1 (NARG1), and Tbdn100 is a protein that in humans is encoded by the NAA15 gene. NARG1 is the auxiliary subunit of the NatA complex. This NatA complex can associate with the ribosome and catalyzes the transfer of an acetyl group to the Nα-terminal amino group of proteins as they emerge from the exit tunnel.
K(lysine) acetyltransferase 6B (KAT6B) is an enzyme that in humans is encoded by the KAT6B gene.
NatA acetyltransferase(Nα acetyltransferase), is an enzyme that serves to catalyze the addition of acetyl groups to various proteins emerging from the ribosome. Upon translation, the NatA binds to the ribosome and then "stretches" to the front end of the forming, or nascent, polypeptide, where it adds this acetyl group. This acetyl group is added to the front end, or N-terminus of the new protein.
Malpuech facial clefting syndrome, also called Malpuech syndrome or Gypsy type facial clefting syndrome, is a rare congenital syndrome. It is characterized by facial clefting, a caudal appendage, growth deficiency, intellectual and developmental disability, and abnormalities of the renal system (kidneys) and the male genitalia. Abnormalities of the heart, and other skeletal malformations may also be present. The syndrome was initially described by Georges Malpuech and associates in 1983. It is thought to be genetically related to Juberg-Hayward syndrome. Malpuech syndrome has also been considered as part of a spectrum of congenital genetic disorders associated with similar facial, urogenital and skeletal anomalies. Termed "3MC syndrome", this proposed spectrum includes Malpuech, Michels and Mingarelli-Carnevale (OSA) syndromes. Mutations in the COLLEC11 and MASP1 genes are believed to be a cause of these syndromes. The incidence of Malpuech syndrome is unknown. The pattern of inheritance is autosomal recessive, which means a defective (mutated) gene associated with the syndrome is located on an autosome, and the syndrome occurs when two copies of this defective gene are inherited.
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Protein acetylation are acetylation reactions that occur within living cells as drug metabolism, by enzymes in the liver and other organs. Pharmaceuticals frequently employ acetylation to enable such esters to cross the blood–brain barrier, where they are deacetylated by enzymes (carboxylesterases) in a manner similar to acetylcholine. Examples of acetylated pharmaceuticals are diacetylmorphine (heroin), acetylsalicylic acid (aspirin), THC-O-acetate, and diacerein. Conversely, drugs such as isoniazid are acetylated within the liver during drug metabolism. A drug that depends on such metabolic transformations in order to act is termed a prodrug.
N-acetyltransferase 80 is a protein that in humans is encoded by the NAA80 gene. It acetylates the N-terminus of mature actin.
Börjeson-Forssman-Lehmann syndrome (BFLS) is a rare genetic disease that causes intellectual disability, obesity, and growth defects.
Okamoto syndrome (OS), also known as Au–Kline syndrome (AKS), is a very rare autosomal dominant genetic condition characterised by congenital hydronephrosis, low muscle tone, heart defects, intellectual disability and characteristic facial features. Those affected often have neurological and skeletal abnormalities, as well as frequent urinary tract infections. Language and walking are usually delayed. Facial features include prominent, downturned ears, an open, downturned mouth and drooping eyelids (ptosis).