Current Genomics

ISSN: 1389-2029

Current Genomics
Volume 7, Number 6, September 2006

Contents


Understanding the Dynamic Behavior of Genetic Regulatory Networks by Functional Decomposition Pp. 333-341
W. Longabaugh and H. Bolouri
[Abstract]


Genetics of Primary CoQ₁₀ Deficiency Pp. 343-349
A.B. Naini, C.M. Quinzii, P. Navas, S. DiMauro and M. Hirano
[Abstract]


Lassa Virus Genome Pp. 351-379
I.S. Lukashevich and M.S. Salvato
[Abstract]


Therapeutic Strategies for the Treatment of Spinal Muscular Atrophy (SMA) Disease Pp. 381-386
F. Sangiuolo, A. Botta, A. Filareto, P. Spitalieri and G. Novelli
[Abstract]


The Emerging Importance of DNA Helicases to Stabilize the Replication Fork Pp. 387-398
R. Gupta, S. Sharma and R.M. Brosh, Jr.
[Abstract]




Abstracts


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Understanding the Dynamic Behavior of Genetic Regulatory Networks by Functional Decomposition
W. Longabaugh and H. Bolouri

A number of mechanistic and predictive genetic regulatory networks (GRNs) comprising dozens of genes have already been characterized at the level of cis-regulatory interactions. Reconstructions of networks of 100’s to 1000’s of genes and their interactions are currently underway. Understanding the organizational and functional principles underlying these networks is probably the single greatest challenge facing genomics today. We review the current approaches to deciphering large-scale GRNs and discuss some of their limitations. We then propose a bottom-up approach in which large-scale GRNs are first organized in terms of functionally distinct GRN building blocks of one or a few genes. Biological processes may then be viewed as the outcome of functional interactions among these simple, well-characterized functional building blocks. We describe several putative GRN functional building blocks and show that they can be located within GRNs on the basis of their interaction topology and additional, simple and experimentally testable constraints.


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Genetics of Primary CoQ₁₀ Deficiency
A.B. Naini, C.M. Quinzii, P. Navas, S. DiMauro and M. Hirano

Coenzyme Q₁₀ (CoQ₁₀) is a lipophilic component of the mitochondrial respiratory enzyme chain, which transfers electrons to complex III (cytochrome bc₁ complex) from complex I (NADH-CoQ reductase), complex II (succinate dehydrogenase), and from the oxidation of fatty acids and branched-chain amino acids via flavin-linked dehydrogenases. Additional cellular functions of CoQ₁₀ have been described. Deficiency of CoQ₁₀ in muscle has been identified in patients with a spectrum of encephalomyopathies ranging from predominant cerebellar ataxia to pure myopathy. In a family with two children affected by infantile-onset encephalomyopathy and nephropathy, the first mutation in a CoQ biosynthetic gene, COQ2, was identified, thus proving the existence of primary CoQ₁₀ deficiency. This article reviews the current state-of-knowledge regarding biochemical and molecular genetic features of inherited CoQ₁₀ deficiency.


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Lassa Virus Genome
I.S. Lukashevich and M.S. Salvato

Lassa virus (LASV), the most dangerous human pathogen among the Arenaviridae, belongs to a complex of genetically related virus strains responsible for the deaths of thousands of people in West Africa each year. The virus has a bi-segmented (L and S) single-stranded RNA genome. Each segment contains two genes in ambisense orientation. The L RNA encodes a large protein, L, or RdRp and a small zinc-binding, Z protein. The S RNA encodes the major structural proteins, nucleoprotein (NP) and glycoprotein precursor (GPC), cleaved into signal peptide, GP1, and GP2 glycoproteins. Genetic diversity among LASV strains is the highest within the family Arenaviridae and NP and RdRp genes are the most variable among LASV genes. The LASV genetic diversity is a great challenge for vaccine development.

In addition to LASV and the prototype lymphocytic choriomeningitis virus (LCMV), the Old World group of arenaviruses includes three other related viruses, Mopeia (MOPV), Mobala (MOBV), and Ippy (IPPYV). These viruses as well as a MOP/LAS reassortant carrying the L RNA segment from MOPV and S RNA segment from LASV are non-pathogenic for experimental animals and are able to induce protective immunity against LASV. Lassa Fever pathogenesis is a sum of the effects induced by viral replication and immune response. The goal of this review is to cover recent publications on viral and host genes that control LASV virulence. The full-length genome sequence of LASV isolates and LASV-related non-pathogenic arenaviruses will provide a useful genetic tool to map LASV genes involved in virulence and to gain insight into phylogeny and evolution of the Old World arenaviruses.


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Therapeutic Strategies for the Treatment of Spinal Muscular Atrophy (SMA) Disease
F. Sangiuolo, A. Botta, A. Filareto, P. Spitalieri and G. Novelli

Spinal Muscular Atrophy (SMA) is a progressive neurodegenerative disorder characterised by the loss of upper and/or lower motor neurons. SMA is the leading genetic cause of infant mortality with an incidence of 1 in 6000 live births and a carrier frequency of about 1 in 50. Different types of disease (from SMAI to SMAV) have been described based on clinical severity and age of onset. The SMA-determining gene, Survival of Motor Neurons (SMN), is part of a 500 kb-inverted duplication on chromosome 5q13. Within the duplicated genes SMN1 and SMN2 can be found. Most (95%) SMA patients have deletions or conversion events of SMN1. The SMN2 gene primarily produces a transcript which lacks exon 7 and of which only 10-20% of its protein is functional.

Although a variety of therapeutic trials are ongoing, only life-prolonging treatments are being developed. The knowledge gained regarding the pathogenesis of SMA remains limited, because the precise function of SMN is not yet known. Furthermore, it is not quite clear why motor neurons of the patients are the only cell type for which SMN expression level are unadequate for their normal activity, even if the affected genes have “housekeeping” functions.

Both pharmacological or genetic approaches have been conducted for the therapy of SMA. Moreover, stem cells provide a further aspect to be analysed. In fact, the genetic modification of a small number of stem cells could give rise to a dividing population of therapeutic cells.

These innovative approaches when united could be usefully adopted to replace lost cells and at the same time protect surviving motor neurons in SMA patients.


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The Emerging Importance of DNA Helicases to Stabilize the Replication Fork
R. Gupta, S. Sharma and R.M. Brosh, Jr.

DNA helicases have historically been implicated in the initiation or elongation phases of DNA replication; however, elegant studies in prokaryotic systems have suggested more specialized functions of helicases to stabilize the replication fork when DNA replication is impeded. More recently, it has become increasingly evident that eukaryotic DNA helicases function at replication forks to participate in processes that include DNA damage detection and signaling, resolution of alternate DNA structures, fork regression, and replication restart. Genetic and biochemical studies have begun to elucidate the molecular roles of DNA helicases at the replication fork in the coordination of the synthesis and processing of leading and lagging strand, a vital function to preserve genomic integrity. In addition, ATP-dependent chromatin remodeling by helicase-like proteins during replication initiation, elongation, or restart may have important roles as well. These themes will be discussed with an emphasis on the cellular mechanisms of DNA helicases/chromatin remodeling enzymes implicated in human disease and proposed to function with other protein factors during replication.