ADVANCES IN THE STUDY OF GENETIC DISORDERS Edited by Kenji Ikehara Advances in the Study of Genetic Disorders Edited by Kenji Ikehara Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2011 InTech All chapters are Open Access distributed under the Creative Commons Attribution 3.0 license, which permits to copy, distribute, transmit, and adapt the work in any medium, so long as the original work is properly cited. After this work has been published by InTech, authors have the right to republish it, in whole or part, in any publication of which they are the author, and to make other personal use of the work. Any republication, referencing or personal use of the work must explicitly identify the original source. As for readers, this license allows users to download, copy and build upon published chapters even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. 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ISBN 978-953-307-305-7 Contents Preface IX Part 1 Background of Genetic Disorder 1 Chapter 1 Origin of the Genetic Code and Genetic Disorder 3 Kenji Ikehara Chapter 2 Inbreeding and Genetic Disorder 21 Gonzalo Alvarez, Celsa Quinteiro and Francisco C. Ceballos Chapter 3 Cytogenetic Techniques in Diagnosing Genetic Disorders 45 Kannan Thirumulu Ponnuraj Chapter 4 Functional Interpretation of Omics Data by Profiling Genes and Diseases Using MeSH–Controlled Vocabulary 65 Takeru Nakazato, Hidemasa Bono and Toshihisa Takagi Chapter 5 Targeted Metabolomics for Clinical Biomarker Discovery in Multifactorial Diseases 81 Ulrika Lundin, Robert Modre-Osprian and Klaus M. Weinberger Part 2 Unifactorial or Unigenetic Disorder 99 Chapter 6 Thalassemia Syndrome 101 Tangvarasittichai Surapon Chapter 7 Genomic Study in β-Thalassemia 149 Saovaros Svasti, Orapan Sripichai, Manit Nuinoon, Pranee Winichagoon and Suthat Fucharoen Chapter 8 HMG–CoA Lyase Deficiency 169 Beatriz Puisac, María Arnedo, Mª Concepción Gil-Rodríguez, Esperanza Teresa, Angeles Pié, Gloria Bueno, Feliciano J. Ramos, Paulino Goméz-Puertas and Juan Pié VI Contents Chapter 9 Mitochondrial HMG–CoA Synthase Deficiency 189 María Arnedo, Mónica Ramos, Beatriz Puisac, Mª Concepción Gil-Rodríguez, Esperanza Teresa, Ángeles Pié, Gloria Bueno, Feliciano J. Ramos, Paulino Gómez-Puertas and Juan Pié Chapter 10 Alström Syndrome 205 Cristina Maria Mihai, Jan D. Marshall and Ramona Mihaela Stoicescu Chapter 11 Alpha One Antitrypsin Deficiency: A Pulmonary Genetic Disorder 227 Michael Sjoding and D. Kyle Hogarth Chapter 12 Tangier Disease 239 Yoshinari Uehara, Bo Zhang and Keijiro Saku Chapter 13 Fabry Disease: A Metabolic Proteinuric Nephropathy 255 Jonay Poveda Nuñez, Alberto Ortiz, Ana Belen Sanz and Maria Dolores Sanchez Niño Chapter 14 Fabry Cardiomyopathy: A Global View 277 Rocio Toro Cebada, Alipio Magnas and Jose Luis Zamorano Chapter 15 The Multifaceted Complexity of Genetic Diseases: A Lesson from Pseudoxanthoma Elasticum 289 Daniela Quaglino, Federica Boraldi, Giulia Annovi and Ivonne Ronchetti Part 3 Multifactorial or Polygenic Disorder 319 Chapter 16 Peroxisomal Biogenesis: Genetic Disorders Reveal the Mechanisms 321 Manuel J. Santos and Alfonso González Chapter 17 Repair of Impaired Host Peroxisomal Properties Cropped Up Due to Visceral Leishmaniasis May Lead to Overcome Peroxisome Related Genetic Disorder Which May Develop Later After Treatment 333 Salil C. Datta, Shreedhara Gupta and Bikramjit Raychaudhury Chapter 18 Genetic Basis of Inherited Bone Marrow Failure Syndromes 357 Yigal Dror Chapter 19 Bernard Soulier Syndrome: A Genetic Bleeding Disorder 393 Basma Hadjkacem, Jalel Gargouri and Ali Gargouri Contents VII Chapter 20 Prader–Willi Syndrome, from Molecular Testing and Clinical Study to Diagnostic Protocols 409 Maria Puiu and Natalia Cucu Chapter 21 Turner Syndrome and Sex Chromosomal Mosaicism 431 Eduardo Pásaro Méndez and Rosa Mª Fernández García Chapter 22 Microstomia: A Rare but Serious Oral Manifestation of Inherited Disorders 449 Aydin Gulses Preface All life on the Earth, including the human race, originated from one common ancestor (comonote) which appeared on the primitive earth about 3.8~4.0 billion years ago after chemical evolutions from simple inorganic to complex organic compounds. The first life successively evolved from simple to complex organisms, such as prokaryotes, mono-cellular eukaryotes, multi-cellular micro-organisms, plants, animals and human beings. Human beings appeared on this planet between 25 and 7 million years ago and have suffered from many kinds of disease for a long time, many of which might lead to death, such as lethal viruses like smallpox and influenza and infectious bacteria like as cholera and tuberculosis. However, human beings have acquired intelligence so as to understand scientifically many concerns in various kinds of fields, including the medical sciences. Thus, human beings actually acquired the knowledge of viruses and micro-organisms to fight against diseases. Many people have seriously hoped to live as long as possible and even to get eternal life with the acquisition of intelligence. It is well-known in Asian countries that Shi Huángdì (BC259-BC210), who was an emperor in ancient China, tried to get eternal life and took various kinds of chemicals. Human beings were protected from infection by viruses - such as the smallpox virus - by the intravenous injection of vaccines into their bodies. Owing to the medical technology of vaccines - which were first discovered by Jenner in 1796 - many lives were saved. Furthermore, penicillin - one of the antibiotics - was first discovered by Fleming in 1881. Subsequently, many kinds of antibiotics - such as streptomycin and kanamycin - were discovered. Consequently, many people were also released from diseases caused by infectious bacteria and many lives were saved, since many patients were even cured of infectious diseases which lead to death through taking the antibiotics. In these ways, the development of medical technologies and medicines has protected human beings from many kinds of diseases caused by the infection of viruses and bacteria, resulting in extending the life span of human beings. Currently, many Japanese people can live until between 90 and 100 years old. For example, the average life spans of females and males living in Japan had reached 86.4 and 79.6 years old by 2009, respectively, while the comparative figures in 1950 were about only 62 and 58 years old, respectively. X Preface It is reported that the highest cause of Japanese deaths is malignant tumour or cancer. Cancers induced by genetic defects leading to deviation from the normal control of cell division can be regarded as a kind of genetic disorder. The genetic defects may occur in all organs, such as the kidney, the spleen, the stomach, the lung and the intestine etc. In addition, it is quite difficult to cure these cancers by the usual treatments such as administration of medicines (except for removal of malignant tumours by surgical operations) because at the present time it is impossible to site-specifically replace the substituted bases to the original/normal bases. This is the reason why cancers are at the top of the Japanese death causes although human beings are released from many kinds of infectious diseases. Many genetic disorders are caused by base substitutions on double-stranded DNA, as with cancers. Although the mutated bases must be replaced with the original/normal bases in order to completely cure the disorders, it is quite difficult to achieve this purpose at the present time, again, as with the case of cancers as described above. Thus, genetic disorders remain diseases which are difficult to cure. In addition, mutations causing genetic disorders may occur in any cells carrying genetic elements or DNA and at anytime. Therefore, the organisms living on earth have been exposed to danger-generating base substitutions without exception, and genetic disorders may be induced in any organs because human beings are multi-cellular organisms. There are two big problems with genetic disorders. One is that it is quite difficult to cure them, as described above. However, in addition to the knowledge about such mechanisms as DNA replication, transcription and the translation of genetic information, human beings have rapidly accumulated knowledge about the base substitutions or mutations occurring on chromosomal DNA which cause various genetic diseases, ever since Watson and Crick discovered the double-stranded structure of DNA in 1956. This knowledge is always significant because it may helpful in devising another medical treatment to cure genetic disorders. Surely, there exist several examples that the knowledge retrieved symptoms or succeeded even to save of patients suffered by genetic disorders. For example, many of the genetic disorders caused by abnormalities of metabolic enzymes could be relieved by going on a diet, which restricts the excess accumulation of the metabolite as a substrate of the enzyme and/or supplies a decreased metabolite as a product of the enzyme. In the case of a genetic disorder causing an excess accumulation of metabolites, it may be also useful to employ the intravenous administration of medicine, which can reduce the formation of toxic metabolites. Another one is a problem accompanied by the recent development of genetic analysis for the diagnosis of genetic disorders, because it has made it possible to judge whether a patient is a carrier or non-carrier of an incurable genetic disease, which may lead to death after several years. A patient who has been able to confirm by their diagnosis as a non-carrier of a genetic disorder can live in peace. However, a patient, who has been proven to be a carrier of a genetic disorder must live with continual uneasiness with regard to confronting their coming death during their remaining life, since the patient [...]... the creation of entirely new proteins intimately related to the creation of entirely new genes These new concepts on the origins of the genetic code, proteins and genes led to the GADV hypothesis on the origin of life 5 GNC primeval genetic code and origin of life In this Section, I will describe briefly GADV hypothesis on the origin of life, since the hypothesis, which I have proposed, is intimately... consanguineous couples and their progeny suppose about 10.4 % of 22 Advances in the Study of Genetic Disorders the 6.7 billion global population of the world (Bittles & Black, 2010) First-cousin marriage and other types of consanguineous unions are frequent in a number of current populations from different parts of the world The extent of inbreeding of an individual is usually measured in terms of his... recognise themselves as being a carrier of a genetic disorder as well as their impending death However, I believe that it is important for the patient to know whether he or she is a carrier or non-carrier of even a genetic disorder resulting in death in the future, because the patient can do their best against the disease during their remaining life based on the state of knowledge regarding the genetic. .. in coding regions, because I would like to discuss on relationships among robustness of the universal genetic code, base substitutions in codons and genetic disorders from a stand point of the origin of the genetic code Term of the universal genetic code”, which is widely used in extant organisms, is used in this Chapter, instead of the standard genetic code”, which is used in many textbooks of in. .. that the genetic code is the most important facility in the fundamental life system Understanding of the origin and evolutionary processes of the genetic code should be quite important to know a framework of the genetic code and a relationship between amino acid substitutions and one-base substitutions causing genetic disorders Fig 4 Role of the genetic code playing in the fundamental life system of. .. transferred into mRNA is translated to the corresponding amino acid sequence of a protein (Step 3) through genetic code mediating genetic information and catalytic function The universal genetic code used by extant organisms on the earth is composed of 64 codons and 20 amino acids (see Table 2) 3 Origin of the Genetic Code (GNC-SNS primitive genetic code hypothesis) Our studies on the origin of the genetic. .. observed in OTCD were obtained from Natural Variants in Protein Knowledgebase (UniProKB) at the address of http://www.uniprot.org/uniprot/P00480 8 Conclusion The genetic disorders upon one-base substitutions in genes encoding amino acid sequences of proteins are induced by the base substitutions at the second codon position more 20 Advances in the Study of Genetic Disorders frequently than those at the. .. position The fact intimately relates to the robustness of the genetic code, which is derived from the origin and evolutionary process of the genetic code According to the GNC-SNS primitive genetic code hypothesis, which I have proposed, it is considered that the universal genetic code originated from GNC code through SNS code as expanding the code up and down in the genetic code table Due to the origin and... hypothesis on the origin and evolutionary pathway of the genetic code (A) In the hypothesis, it is supposed that the universal genetic code originated from GNC primeval genetic code through SNS primitive genetic code Elucidation of the most primitive GNC code made it possible to propose as GADV hypothesis on the origin of life (B) Alternative representation of the origin and evolutionary pathway of the. .. treatment The mutations causing the genetic disorders are scattered throughout genes and their neighboring regions as shown in Figure 1 (A) It is also known that many genetic diseases are induced by single-base substitutions or missense mutations including nonsense mutations in genetic regions encoding amino acid sequences of proteins For instance, sickle-cell anemia, one of the classical genetic disorders, . expression leading to synthesis of lower or higher amounts of proteins than normal level, resulting in many kinds of genetic diseases (Figure 1 (A)). Advances in the Study of Genetic Disorders. among robustness of the universal genetic code, base substitutions in codons and genetic disorders from a stand point of the origin of the genetic code. Term of the universal genetic code”, which. suffered by the rarely occurring genetic disorders. This makes a quite big problem of the genetic disorders from a stand point of medical treatment. The mutations causing the genetic disorders