Glycobiology: Toward Understanding the Function of Sugars.

Glycosylation in Cellular Mechanisms of Health and Disease

We present a DNA library preparation method that has allowed us to reconstruct a high-coverage (30×) genome sequence of a Denisovan, an extinct relative of Neandertals. The quality of this genome allows a direct estimation of Denisovan heterozygosity indicating that genetic diversity in these archaic hominins was extremely low. It also allows tentative dating of the specimen on the basis of “missing evolution” in its genome, detailed measurements of Denisovan and Neandertal admixture into present-day human populations, and the generation of a near-complete catalog of genetic changes that swept to high frequency in modern humans since their divergence from Denisovans.

https://science.sciencemag.org/content/sci/338/6104/222.full.pdf

A high-coverage genome sequence from an archaic Denisovan individual

Simple and complex carbohydrates (glycans) have long been known to play major metabolic, structural and physical roles in biological systems. Targeted microbial binding to host glycans has also been studied for decades. But such biological roles can only explain some of the remarkable complexity and organismal diversity of glycans in nature. Reviewing the subject about two decades ago, one could find very few clear-cut instances of glycan-recognition-specific biological roles of glycans that were of intrinsic value to the organism expressing them. In striking contrast there is now a profusion of examples, such that this updated review cannot be comprehensive. Instead, a historical overview is presented, broad principles outlined and a few examples cited, representing diverse types of roles, mediated by various glycan classes, in different evolutionary lineages. What remains unchanged is the fact that while all theories regarding biological roles of glycans are supported by compelling evidence, exceptions to each can be found. In retrospect, this is not surprising. Complex and diverse glycans appear to be ubiquitous to all cells in nature, and essential to all life forms. Thus, >3 billion years of evolution consistently generated organisms that use these molecules for many key biological roles, even while sometimes coopting them for minor functions. In this respect, glycans are no different from other major macromolecular building blocks of life (nucleic acids, proteins and lipids), simply more rapidly evolving and complex. It is time for the diverse functional roles of glycans to be fully incorporated into the mainstream of biological sciences.

/pdf/biological-roles-of-glycans-zowb8sw07y.pdf

Biological Roles of Glycans

Intracellular membrane traffic defines a complex network of pathways that connects many of the membrane-bound organelles of eukaryotic cells. Although each pathway is governed by its own set of factors, they all contain Rab GTPases that serve as master regulators. In this review, we discuss how Rabs can regulate virtually all steps of membrane traffic from the formation of the transport vesicle at the donor membrane to its fusion at the target membrane. Some of the many regulatory functions performed by Rabs include interacting with diverse effector proteins that select cargo, promoting vesicle movement, and verifying the correct site of fusion. We describe cascade mechanisms that may define directionality in traffic and ensure that different Rabs do not overlap in the pathways that they regulate. Throughout this review we highlight how Rab dysfunction leads to a variety of disease states ranging from infectious diseases to cancer.

Role of Rab GTPases in membrane traffic and cell physiology.

Phosphomannomutase deficiency is a cause of carbohydrate-deficient glycoprotein syndrome type I.

Congenital disorders of glycosylation (CDG) are a large family of genetic diseases resulting from defects in the synthesis of glycans and in the attachment of glycans to other compounds. These disorders cause a wide range of human diseases, with examples emanating from all medical subspecialties. Since our 2001 review on CDG (36), this field has seen substantial growth: The number of N-glycosylation defects has doubled (from 6 to 12), five new O-glycosylation defects have been added to the two previously known ones, three combined N- and O-glycosylation defects have been identified, the first lipid glycosylation defects have been discovered, and a new domain, that of the hyperglycosylation defects, has been introduced. A number of CDG are due to defects in enzymes with a putative glycosyltransferase function. There is also a growing group of patients with unidentified defects (CDG-x), some with typical clinical presentations and others with presentations not seen before in CDG. This review focuses...

Congenital Disorders of Glycosylation: A Rapidly Expanding Disease Family

Sialic acid-deficient serum and cerebrospinal fluid transferrin in a newly recognized genetic syndrome

Congenital (genetic) disorders of glycosylation (CDG) are a rapidly growing disease family, with some 45 members reported since its first clinical description in 1980. Most of these are protein hypoglycosylation diseases, but recently three defects in lipid glycosylation have been identified. Most protein hypoglycosylation diseases are due to defects in the N-glycosylation pathway (16 diseases). The remaining ones affect the O-glycosylation pathway (8 diseases), both the N- and the O-glycosylation pathways, or other pathways (17 diseases). CDG can affect nearly all organs and systems, but there is often an important neurological component. The first-line screening for the N-glycosylation diseases is serum transferrin isoelectrofocusing (IEF), and for the O-glycosylation disorders apo CIII IEF. It has to be stressed that a normal test result does by no means exclude a CDG. In case of an abnormal result and as long as the basic defect has not been elucidated, the disease is labeled CDG-x (CDG-Ix when the transferrin IEF shows a type 1 pattern, and CDG-IIx when it shows a type 2 pattern).

/pdf/congenital-disorders-of-glycosylation-3i6wpc265j.pdf

Congenital Disorders of Glycosylation

Identical twin-sisters (born at 36 wks; birthweight 2.2 and 3.0 kg) presented at 2 years of age with marked psychomotor retardation and bone-age of 1 year. Physical growth and phenotype were normal. Repeated investigations revealed: markedly fluctuating basal serum prolactin (778-5652 μU/ml; nl < 800), FSH (17-55 mIU/ml; nl < 10) and GH (2-144 ng/ml; nl < 10), but normal LH; low TBG (1.1 and 1.2 mg/dl; nl 1.6-2.4) also present in the father, with otherwise normal thyroid function including TRH test, arylsulphatase A moderately increased in serum (mean 293 and 272 nmol/ml; nl 30-130) but not in leukocytes, without increase of other lysosomal enzymes, and increasing CSF protein. Normal results were found for GH response to i.m. glucagon, urinary excretion of 17-keto and 17-hydroxysteroids, at funduscopy and for lymphocyte karyotype (Giemsa banding), buffy coat of blood leukocytes and electronmicroscopy of conjunctiva. Sella tursica was normal on x-ray. Cortical and cerebellar hypotrophy was evident on CAT-scan. Electromyography was normal but nerve conduction velocity was delayed (30-31 m/sec; nl 50 ± 1). A nerve and muscle biopsy is planned. At this stage we have no satisfactory explanation for these unusual findings.

/pdf/familial-psychomotor-retardation-with-markedly-fluctuating-1ytpl0uu55.pdf

Familial psychomotor retardation with markedly fluctuating serum prolactin, FSH and GH levels, partial TBG-deficiency, increased serum arylsulphatase A and increased CSF protein: a new syndrome?: 90

Jaak Jaeken

Papers

Phosphomannomutase deficiency is a cause of carbohydrate-deficient glycoprotein syndrome type I.

Congenital Disorders of Glycosylation: A Rapidly Expanding Disease Family

Sialic acid-deficient serum and cerebrospinal fluid transferrin in a newly recognized genetic syndrome

Congenital Disorders of Glycosylation

Familial psychomotor retardation with markedly fluctuating serum prolactin, FSH and GH levels, partial TBG-deficiency, increased serum arylsulphatase A and increased CSF protein: a new syndrome?: 90