DNA and You

Gene Found for Ghosal Hematodiaphyseal Dysplasia Syndrome: A Rare Syndrome with Increased Bone Density

A paper published online on Sunday in the journal Nature Genetics (abstract available here) describes the identification of mutations in a gene causing the rare, autosomal recessive, genetic syndrome Ghosal hematodiaphyseal dysplasia syndrome (GHDS).  GHDS is a disorder of increased bone density. 

The authors had previously mapped the disease gene to a segment of chromosome 7 by studying two families from Algeria and Tunisia.  In this study, they identified mutations in TBXAS1 - which encodes the enzyme thromboxane synthase - in the two original families, in addition to two other families from Tunisia and Pakistan with GHDS. 

Thromboxane synthase is one of the terminal enzymes in the arachidonic acid cascade and is involved in the production of thromboxane A2, which is known to be a powerful inducer of blood platelet aggregation in addition to having other physiologically important effects. 

The demonstration that TBXAS1 mutations cause GHDS, a disorder of increased bone density, suggests that thromboxane synthase and thromboxane A2 may play an important role in bone remodeling. 

Additionally, as is often the case with the identification of disease genes causing rare Mendelian (see "Mendelian trait" section of this article) syndromes, this paper suggests a candidate gene for a related, but much more common, condition; the involvement of TBXAS1 in a disorder of increased bone density suggests that it may be a candidate gene worth investigating in osteoporosis in the future.

More NEJM Genomics: High-Throughput Sequencing Utilized to Identify a New Arenavirus in Transplant-Associated Infections

In a new paper by Gustavo Palacios and colleagues published in the New England Journal of Medicine, the 454 Life Sciences (Roche) high-throughput sequencing platform was utilized to investigate the cause of a fatal febrile illness in three patients who died about a month after receiving transplanted organs from the same donor (abstract here).  This approach allowed the identification of a new arenavirus transmitted through solid-organ transplantation that is likely responsible for the fatal infections in these transplant recipients.  An accompanying editorial (available to subscribers only) points out that the application of high-throughput sequencing technologies may transform the clinical microbiology lab.  Dr. Richard Whitley suggests several clinical conditions caused by infectious diseases that may be particularly amenable to a high-throughput sequencing diagnostic approach: particularly central nervous system encephalitis and acute respiratory tract infections.

Genetics Takes Over The New England Journal of Medicine...Again

There has been a sustained trend towards the publication of more and more genetics and genomics-related papers in The New England Journal of Medicine.  Last month I commented on it here.  This week's issue of the NEJM is no exception:

• There is a very interesting pharmacogenetics paper (abstract here) focused on the genetic basis of hypersensitivity reactions to abacavir, an important anti-retroviral drug utilized in the treatment of HIV.  About 5-8% of individuals of northern European descent develop a serious hypersensitivity reaction, mediated by their immune system, in the first 1-1/2 months of abacavir treatment.  Severe adverse drug reactions, whether occurring in the context of treatment with abacavir or with any of a number of other drugs, have a significant impact on morbidity, mortality, and total costs to our healthcare system and society.  In 2002, medical researchers determined that the HLA-B*5701 variant of the Human Leukocyte Antigen (HLA)-B gene was highly associated with abacavir hypersensitivity reactions, which are unpleasant and characterized by fever, rash, gastrointestinal symptoms, respiratory symptoms, and other constitutional symptoms.  Although several previous studies had suggested that genotyping for HLA-B*5701 (which can be done with DNA sequencing-based methods), could help to significantly reduce abacavir treatment-related hypersensitivity reactions, the present study was an impressively sized, randomized, double-blind, prospective study evaluating the clinical utility of HLA-B*5701 genotyping prior to abacavir treatment in HIV infection.  The HLA-B*5701 allele was found in 5.6% of patients (predominantly white).  This screening was able to eliminate abacavir-related hypersensitivity reactions in the prospective HLA-B*5701 screening group.  Thus, the study showed that in predominantly white populations, ~94% of patients do not have HLA-B*5701 and, therefore, have a low risk of hypersensitivity reaction to abacavir.  Likewise, the test can be utilized to prevent the toxic effect of the drug in the 6% of individuals with HLA-B*5701.   
• Another paper by Dr. William Gahl (from the NHGRI) and colleagues focuses on the natural history of the remarkable Hutchinson-Gilford Progeria (premature aging) Syndrome (H-GPS).  Although H-GPS (meet some kids with H-GPS here) is an extraordinarily rare genetic syndrome, the detailed description in this paper may significantly impact our description of normal aging.  I'll try to return to this subject in another post.
• A paper (abstract available here) by Dr. Stephen Kaler (of the NICHD) and colleagues describes attempts at early diagnosis and treatment of neonatal Menkes disease, a genetic disorder of copper transport.  This disease is caused by mutations in the copper-transporting gene, ATP7A.  The clinical symptoms in Menkes disease are secondary to decreased activity of enzymes that require copper as a cofactor.  Because early detection with newborn screening is not available and because infants with Menkes disease appear normal for a period of about 2 months prior to clinical deterioration, researchers have sought better methods of early diagnosis.  The need is underscored by the fact that outcomes may be improved in this disease if daily copper injections are started very soon after birth.  Dr. Kaler and colleagues utilized measurements of neurochemicals in blood plasma during the neonatal period to improve early diagnosis of Menkes disease.  Specifically, they showed that measurements of plasma catecholamines in infants at risk has both high sensitivity and high specificity, even in the period before infants become symptomatic.  Lastly, they also present evidence suggesting that response to copper treatment in these infants may depend on genotype: infants with mutations that do not completely destroy the function of the ATP7A copper transporter appear may be particularly responsive to early copper treatment.