ADVERTISEMENT

An Old Problem And The Lives Of Hemophiliacs With Recurrent Hemorrhages

The Problem

Finding the ways in which changes in the genetic material (genotype) affects the structure and function of a given organism (phenotype) is the subject of very old attention, starting with the publication of the person who is considered the father of genetics, the priest Gregor Mendel (1822-1884). The year of the publication was 1866, so the inquiry is lasting for 151 years.

The Pathology

Human variation can be classified into two large groups, normal and pathological. The characteristic that was the subject of the article, hemophilia B (HB), is the less frequent (about 30%) of a clotting disorder that was recognized as a distinct pathology for many years now (the most frequent, around 70% of the cases, is hemophilia A, HA).

ADVERTISEMENT

The familial character of the hemophiliacs, in general, was already recognized in the Talmud, the Jewish holy book, which dispensed babies from circumcision if the mother had relatives with hemorrhages; and its inheritance was clearly characterized by C. F. Nasse in 1820, therefore, four decades before Mendel’s publication.

Our research group has been interested in this pathology for more than half a century, and the beginning of the investigations was led by Israel Roisenberg (1934-2013). The present series of studies started with a 2009 paper, and the one which is being considered is the seventh. The series objective is the molecular characterization of the mutations responsible for the different clinical pictures of hemophilia patients, but we also investigated the factors that may influence the development of antibodies (inhibitors) against the substance used for the replacement of the missing or decreased factor. This complication, however, occurs only in HA patients, being very infrequent in HB.

The Study

Coagulation Factor IX, missing or decreased in HB, is synthesized in the hepatocytes as a precursor protein of 461 amino acids, and after appropriate processing presents four domains: GLA (gamma-carboxyglutamic acid), EGF-like (epidermal growth factor-like), and serine protease. The type of the mutation that is going to affect any one of these regions can also be classified whether: a) they affect only the processing of the protein (splicing sites); b) lead to coding errors (non-sense); c) to a different pattern in the processing and determination of the protein (frameshift); or d) to a different type of amino acid (missense). Depending on the type of mutation and the region of the protein that is going to be affected, different clinical patterns emerge.

We tested 43 Brazilian HB patients whose clinical conditions were classified as severe (30), moderate (7) or mild (6). A total of 31 types of mutations were detected in them, and all of them would lead to structural changes in the protein, such as spacing between units, incorrect folding or binding changes, as well as charge and hydrophobicity modifications. Their position (namely, near or distant from sites of interaction with other coagulation factors) is also important.

ADVERTISEMENT

Six of the 31 mutations had not been previously described in the literature, and detailed molecular information about them, as well as models for the interpretation of the four new missense mutations found (comparing the normal and mutant proteins), were provided.

The Importance

So far, so good. However, what is the importance of these findings for the patients themselves, their families, or science in general?

The answers are as follows: a) Improved diagnosis: the finer subdivisions obtained would allow a better comparison between patients with the same mutation in terms of clinical severity and of prospects for the future; b) Improved genetic counseling: the determination of the exact change would allow a more precise and cheaper search for the presence or not of the allele in female potential carriers; and c) Gene therapy: with the progress in the techniques of gene editing, it will be possible, in the future, to correct the specific change which occurred with gene therapy methods, leading to the patient’s cure.

This study, Molecular characterization of haemophilia B patients in southern Brazil was recently published in the journal Haemophilia.

ADVERTISEMENT

Comments

READ THIS NEXT

Within-host Competition Slows Evolution Of Drug Resistance In Malaria

Most cases of malaria can be cured with a simple course of antimalarial drugs, but many of these drugs have […]

A Novel Five-Node Feed-Forward Loop Delves Into The Molecular Mechanism Of Ischemic Stroke

  When Robert Hooke first discovered cells in a sliver of cork, one would have barely imagined that this microscopic […]

New Toulouse-Led Scientific Study Reveals Drosophila melanogaster Can Transmit Sexual Preferences Culturally Over The Long Term

A Toulouse-led interdisciplinary research consortium shows that the fruit fly has all the cognitive capacities to culturally transmit their sexual […]

Corrosion Inhibition By Essential Oil Extracts: A Sustainable Method Of Controlling Carbon Steel Degradation

Published by Roland Loto Department of Mechanical Engineering, Covenant University, Ota, Ogun State, Nigeria These findings are described in the […]

Traitorous Eyes

A twin study suggests that DNA also controls how well one can spot thoughts and emotions in the eyes of […]

Mucosal Immunoglobulin: An Important Tool In The Olfactory Organ Of Teleost Fish To Fight The Protozoan, Ichthyophthirius multifiliis

Olfaction is a very important chemoreception that forms the sense of smell in animals. Terrestrial animals can detect low concentrations […]

Amazonite: Green Mineral Named After The Amazon River

The Amazonite stone is a green mineral that is named after the Amazon River in South America. This green mineral […]

Science Trends is a popular source of science news and education around the world. We cover everything from solar power cell technology to climate change to cancer research. We help hundreds of thousands of people every month learn about the world we live in and the latest scientific breakthroughs. Want to know more?