Biennial and Annual Report on the Rare Diseases Research Activities at the National Institutes of Health FY 2004

National Human Genome Research Institute (NHGRI)

Overview of Rare Diseases Research Activities

The National Human Genome Research Institute (NHGRI) led the National Institutes of Health’s (NIH) contribution to the International Human Genome Project (HGP). With the achievement of its final goal, the finished sequence of the human genome in April 2003, this project was successfully completed ahead of schedule and under budget and has already begun to change the way we address rare diseases.

In October 2004, the International Human Genome Sequencing Consortium, led in the United States by the NHGRI and the Department of Energy, published an analysis of that finished human genome sequence in the journal Nature. This analysis reduces the estimate of the number of human protein-coding genes from 35,000 to only 20,000–25,000—a surprisingly low number for our species, considering that only a decade ago most scientists thought we had over 100,000 genes.

The NHGRI has moved forward into the genomic era with a wide range of powerful new extramural research initiatives that will accelerate genome research and its application to human health. As well, in its Division of Intramural Research (DIR) scientists are using the techniques and tools produced by the HGP and developing new ones to study the fundamental mechanisms of inherited and acquired genetic disorders, including many rare disorders, to lead ultimately to improved diagnostic, prevention, and treatment strategies.

Inherited Disorders of the Immune System

The NHGRI Genetics and Molecular Biology Branch is conducting a research program to find the causes and develop better treatments for inherited disorders of the immune system. These include immunodeficiencies, in which gene defects impair the ability of the immune system to fight infections, and disorders of immune cell regulation, in which autoimmunity may be seen. Current areas of investigation include severe combined immunodeficiency, hyper-IgE syndrome, certain inherited autoimmune diseases including variants of autoimmune lymphoproliferative disease, and genetic determinants of susceptibility to HIV/AIDS.

Severe Combined Immunodeficiency

This project investigates diagnosis and treatment of severe combined immunodeficiency (SCID). Affected infants have severe infections that are fatal unless the immune system can be restored. Bone marrow transplant (BMT) is life-saving if the disease is detected in time. SCID is most often caused by defects in the X-linked IL2RG gene that encodes the common gamma chain of receptors for cytokines. When this gene is defective, lymphocytes do not develop normally. To know how mutations in the IL2RG gene cause X-linked SCID (XSCID), researchers collect samples of blood or tissue, perform DNA analysis, assess expression of common gamma chain protein, and analyze its function. NHGRI researchers can then perform carrier testing and genetic counseling prenatal diagnosis, making affected infants eligible for improved early treatments.

Despite improved survival with BMTs, many XSCID patients are not completely cured, raising the question whether retroviral gene transfer ex vivo to white blood cells could improve patients' outcomes. NHGRI researchers have a complete XSCID gene therapy program, including vector development, animal models, retroviral transduction optimization, and clinical evaluation of patients who have failed standard BMT treatment, and are treating patients with a clinical gene therapy protocol.

Hyper IgE Syndrome (Job Syndrome)

Hyper-IgE syndrome, also known as Job syndrome after the biblical character who was stricken with boils, is a rare primary immunodeficiency characterized by recurrent skin abscesses, recurrent pneumonia with development of lung cysts, and extreme elevations of serum IgE. The specific immune defect has not been discovered, and NHGRI researchers have undertaken genetic studies to map the disease.

Autoimmune Lymphoproliferative Syndrome

Autoimmune lymphoproliferative syndrome (ALPS) is a rare syndrome in which patients have large lymph nodes and spleens, increased numbers of a rare type of lymphocyte called CD4-/CD8-T cells, or double-negative T cells, and defects in programmed cell death, or apoptosis of their lymphocytes. NHGRI researchers have found that most patients with ALPS have inherited mutations in the apoptosis mediator Fas. These patients' lymphocytes do not die when they should; instead, they accumulate and can attack the body's own tissues. Autoimmune diseases of the red blood cells, platelets, and white blood cells are common in ALPS. NHGRI researchers have found some affected members of ALPS families who are more severely affected than others. Modifying genes that influence severity of ALPS are being sought. Researchers have also found that some patients with no mutation in the Fas gene have defects in related genes such as caspase-10

Developmental Disorders

Hutchinson-Gilford progeria syndrome (HGPS) is the most dramatic human syndrome of premature aging. Children with this rare condition are normal at birth, but by age 2 they have stopped growing, lost their hair, and shown skin changes and loss of subcutaneous tissue that resemble the ravages of old age. They rarely live past adolescence, dying almost always of advanced cardiovascular disease (heart attack and stroke). Using genome-wide scans, NHGRI researchers identified an area on chromosome 1q that was a candidate for HGPS mutations in a subset of patients. After sequencing a plausible candidate gene in the suggested area, the gene for lamin A/C (LMNA), the researchers discovered that nearly all cases of HGPS harbor a de novo point mutation in the LMNA gene. Researchers found that the mutation creates a smaller, truncated version of the lamin A/C protein, which is now referred to as progerin. The researchers have shown that progerin acts in a dominant manner to disrupt the structure of the cell’s nuclear membrane scaffold.

Goldman RD, Shumaker DK, Erdos MR, Eriksson M, Goldman AE, Gordon LB, Gruenbaum Y, Khuon S, Mendez M, Varga R, Collins FS (2004) Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci U S A. 101:8963-8. [Pubmed]

Polydactyly Syndromes

A group of syndromes that include polydactyly with other malformations is the subject of a clinical-molecular study. This research study encompasses a range of phenotypes that include Pallister-Hall syndrome, the allelic disorder Greig cephalopolysyndactyly syndrome (GCPS), McKusick-Kaufman syndrome (MKS), and Bardet-Biedl syndrome (BBS). The clinical manifestations of these disorders include polydactyly, central nervous system malformations (with or without mental retardation and seizures), craniofacial malformations, and visceral malformations such as renal malformations or congenital heart defects. NHGRI researchers study these disorders by a translational approach that begins in the clinic with careful clinical evaluation of the phenotypes by physical examination and imaging studies that include radiographs, ultrasound, MRI, and CT scanning. They have shown that BBS and MKS can both be caused by mutations in the same gene. PHS and GCPS are caused by a wide spectrum of mutations in the GLI3 gene. The severity of the GCPS phenotype, specifically the mental retardation and learning disability, are correlated with these mutations. Patients with larger deletions have a more severe form of the disease. Researchers are also characterizing a mouse mutant that also has phenocopy of the extra toes in a Gli3 mouse mutant but is linked to a gene other than Gli3. This animal could shed light on other genes in the Gli3 pathway.

Lowe Oculocerebrorenal Syndrome

The oculocerebrorenal syndrome of Lowe is a rare X-linked metabolic disorder characterized by congenital cataracts, renal tubular dysfunction, and mental retardation. It is caused by mutations in the gene OCRL1 encoding a specific phosphatase. Research at NHGRI has resulted in the identification of the responsible gene, determination of its biochemical function, and the development of accurate enzymatic diagnosis for affected fetuses and individuals. The current focus of this research is to understand how a defect in this enzyme results in the various manifestations of the syndrome. Researchers are working both in cultured human cells and in animal models. They have demonstrated that the cell structural skeleton is disorganized in cultured cells from Lowe syndrome patients. They are investigating the role of intracellular calcium in bringing about this phenotype and have found abnormal calcium signaling in patient cells. Researchers are also working to create a mouse model for Lowe syndrome.

Hirschsprung Disease

Animals heterozygous for mutations in the SOX10 transcription factor exhibit multiple defects in neural crest development, including reduced numbers of melanocytes in the skin, an absence of myenteric ganglion in the colon, and deafness. A human congenital disorder, Hirschsprung disease, also exhibits rectocolic aganglionosis and can be associated with hypopigmentation caused by SOX10 mutations. Thus SOX10 mice, as well as other neural crest mutant mice, serve as mouse models for this disease. Investigation of the involvement of SOX10 in Hirschsprung disease and other neural crest-related disorders is being explored. NHGRI researchers have established a system for adding genes back to neural crest stem cells in order to complement genetic defects. They plan to use this system to test hierarchial relationships between SOX10 and its target genes and have demonstrated that they can use this system to correct SOX10 defects in vitro.

Microphthalmia Syndromes

The project seeks to understand the clinical and molecular basis of syndromic microphthalmia. This disorder comprises anophthalmia or microphthalmia (small or absent eyes with blindness), mental retardation, and skeletal anomalies. NHGRI researchers have identified a large family affected by Lenz microphthalmia and have mapped the gene to the short arm of the X chromosome. This result is surprising because another family with this disorder maps to the long arm of the X chromosome. This means that Lenz microphthalmia is probably an amalgam of two disorders. Researchers have used positional cloning to isolate the gene that is altered in the condition, which is called BCOR (BCL-6 co-repressor). In addition, researchers have discovered that mutations in this gene also cause the oculo-facio-cardi-dental syndrome. They are currently assessing the functional consequence of these mutations in a zebrafish model system. The results of this research should allow development of accurate diagnostic tests for microphthalmia and improved understanding of eye development

Molecular Genetics of Anabaptist Diseases

Old Order Amish and related Anabaptist sects (including Mennonites) are important for the study of genetic disease as they represent a cultural and genetic population isolate. In addition, they are enthusiastic historians and have excellent printed genealogical records. NHGRI researchers have built the Amish Genealogy Database (AGDB) and several computational tools to analyze the database including PedHunter. These tools allow generation of pedigrees for genetic study in an accurate and rapid fashion. NHGRI researchers have also cloned the genes that are altered in glycogen storage disease type 6, McKusick-Kaufman syndrome, and Amish nemaline myopathy and are currently working on Amish microcephaly. They have identified the gene alteration in Amish microcephaly that codes for a protein that transports deoxynucleotides (DNA precursors) into the mitochondria. They have currently developed both mouse and zebrafish animal models for this disorder and are now characterizing the phenotypes of these organisms.

Proteus Syndrome

Proteus syndrome (PS) is a rare, sporadic syndrome that causes progressive, patchy overgrowth, bony distortion or deformation, tumor predisposition, and mental retardation. NHGRI researchers are determining the natural history and etiology of Proteus syndrome. The natural history and the phenotypic range are being determined by clinical assessment and longitudinal follow-up of a cohort of patients. Very little is known about the natural history and the range of the phenotype of PS. NHGRI scientists are accruing a cohort of patients with PS and overlapping phenotypes and plan to follow them over time. As the disorder is usually apparent at or soon after birth and appears to evolve at least into the 20s, it will be necessary to have long-term follow-up. The etiology of PS has been studied using various comparative molecular biology techniques including representational difference analysis, cDNA arrays, and other techniques. Researchers are currently in the process of analyzing expression array data. The researchers have also performed a retrospective literature review and reclassified all previously published patients according to their new clinical criteria. This analysis shows that the lethality of the disorder is higher than previously believed, affects more males than females, and has a high rate of complications.

Alagille Syndrome

Researchers at NHGRI have shown that mutations in the Jagged1 (JAG1) gene are responsible for Alagille syndrome (AGS), a developmental disorder affecting multiple organ systems including liver, heart, eye, face, and vertebrae. Zebrafish is an excellent model for vertebrate development, and therefore researchers have initiated efforts to explore the role of jagged genes in zebrafish development and in developmental diseases like AGS. As a part of this effort, they have isolated and characterized jagged homologous genes from zebrafish.

Congenital Disorders of Glycosylation

Congenital disorders of glycosylation (CDG) are a diverse group of metabolic disorders presenting with a spectrum of clinical features ranging from severe neurologic manifestations and multisystemic involvement to hypoglycemia and severe gastrointestinal symptoms with normal development. There are now 16 types of CDG defined by distinct enzyme defects and genes. The number of children and adults diagnosed with CDG in the United States is increasing rapidly with a wider variance in the phenotypes. NHGRI researchers will identify and evaluate individual patients with CDG, explore the clinical and biochemical features of untyped individuals and, through clinical research, continue to add to the compendium of clinical management strategies for physicians caring for these affected adults and children.

Neurological Disorders

Familial Encephalopathy with Neuronal Inclusion Bodies

NHGRI researchers are exploring the clinical, laboratory, neuropsyche, and imaging features of at-risk members of families with familial presenile dementia with neuroserpin storage. Over the past year the name of the disorder has been changed to familial encephalopathy with neuronal inclusion bodies (FENIB). At the NIH Clinical Center researchers have seen 25 individuals at risk for this disorder for full clinical evaluations. The clinical facet of this project continues to be a long-term exploration of the natural history of family members at risk. This will increase insight into the pathophysiology and clinical presentation of FENIB. These families provide not only rich clinical insight but the opportunity to understand the controversy surrounding presymptomatic testing in late-onset neurodegenerative disorders. Further clinical delineation and assessment of counselling needs remain the clinical goals for this project. A parallel laboratory project includes the development of a mouse model for FENIB that will further help to elucidate the phenotype and genotypic variation.

Huntington’s Disease

Research suggests that appraisals of a stressful event, such as the likelihood of change and perceived ability to cope, are important predictors of the use of coping strategies and overall adaptation. This NHGRI study explores the relationships between coping self-efficacy, coping strategies, and grief reaction with individuals who have undergone presymptomatic genetic testing for Huntington’s disease (HD). Eligibility criteria included individuals who tested negative or positive and who were currently without symptoms of HD. Measures included the Coping Self-Efficacy Scale, the Ways of Coping Checklist-Revised, and the Grief Experience Inventory. Preliminary regression analysis revealed coping self-efficacy to be negatively associated with the use of avoidance coping and avoidance coping to be positively associated with grief scores. Respondents showed greater use of problem-focused coping strategies compared to emotion-focused strategies. Problem-focused coping strategies were negatively associated with measures of grief, while emotion-focused coping was positively associated with grief scores. An individual’s coping self-efficacy predicts the use of particular coping strategies that in turn can predict the degree of grief experienced. On the basis of this work, genetic counseling interventions have been proposed to maximize coping self-efficacy and effective coping strategies in light of a genetic test result for a condition that has no treatment or cure.

Endocrine Disorders

Multiple Endocrine Neoplasia Type 1

Multiple endocrine neoplasia type 1 (MEN1) is characterized by multiple tumors of the parathyroid, anterior pituitary, and GI endocrine tissues. NHGRI researchers have previously shown that mutations in the MEN1 gene are responsible for the MEN1 syndrome. The MEN1 encoded nuclear protein, Menin, binds the transcription factors JunD and NFκB and can repress JunD and NFκB-induced transcription. By expressing wild-type or mutant JunD in mouse fibroblast cell lines that do not express menin and JunD, NHGRI researchers found that interaction with menin is required for the growth suppressor function(s) of JunD. They have developed both conventional and conditional mouse knockout models that yield phenotypes that are remarkably similar to the human MEN1 disease and have allowed delineation of the stages in tumor development. Researchers have developed tissue-specific menin-inducible transgenic mouse models and are currently creating a drosophila model.

Disorders of Vision

Rieger Syndrome

A continuing area of interest of researchers at NHGRI involves the homeodomain family of proteins, which play a fundamental role in a diverse set of functions that include body plan specification, pattern formation, and cell fate determination during metazoan development. Members of this family are characterized by a helix-turn-helix DNA-binding motif known as the homeodomain. Homeodomain proteins regulate various cellular processes by specifically binding to the transcriptional control region of a target gene.

These proteins have been conserved across a diverse range of species, from yeast to human. A number of inherited human disorders are caused by mutations in homeodomain-containing proteins. One specific homeodomain protein, FOXC1, is implicated in Axenfeld-Rieger malformations. Patients with Axenfeld-Rieger malformations typically show a spectrum of ocular findings, including iris hypoplasia, a prominent Schwalbe line, iris adhesions, and goniodysgenesis. The most severe cases show elevated intraocular pressure, leading to the development of glaucoma. As an outgrowth of the studies on the homeodomain class of proteins, NHGRI researchers have developed and continue to maintain the Homeodomain Resource. This publicly available database provides a curated collection of information that includes full-length homeodomain-containing sequence data, experimentally derived structures, protein-protein interaction data, DNA-binding sites, and mutations leading to human genetic disorders. Work is continuing in this area of homeodomain proteins to better understand these eye-related mutations and their net effect on vision.

Metabolic Disorders

Methylmalonic Acidemia and Related Disorders

Methylmalonic acidemia (MMA) is a genetically heterogeneous disorder of methylmalonate and cobalamin (vitamin B12) metabolism. Symptoms of MMA usually begin in the first few months of life and include lethargy, failure to thrive, vomiting, dehydration, respiratory distress, hypotonia, and hepatomegaly. Acute episodes may include drowsiness, coma, and seizures, with subsequent developmental delays. An NHGRI research study encompasses the hereditary methylmalonic acidemias and cobalamin deficiency disorders. These metabolic disorders are genetically heterogeneous and collectively represent an important subset of the organic acidemias. The general goal of the research is to define the complications seen in patients, replicate the findings in mice or other organisms, and use the combined information to guide the development and testing of new therapies. Researchers study the hereditary methylmalonic acidemias and cobalamin deficiency disorders via a translational approach that includes a clinical and metabolic evaluation of affected patients and use animal models to examine the disorder in the laboratory. In addition, they have developed mouse and worm models of methylmalonic acidemia.

Additional Activities

Genetic and Rare Diseases Information Center

In order to respond to the public’s need for information on genetic and rare disorders, NHGRI and the Office of Rare Diseases, NIH, maintains and supports the NHGRI/ORD Genetic and Rare Diseases Information Center (GARD). The Information Center focuses on meeting the information needs of the general public, including patients and their families, health care professionals, and biomedical researchers. The purposes of the Information Center are to: (1) serve as a central, national repository of information materials and resources on genetic and rare diseases, conditions, and disorders; (2) collect, produce, update, and disseminate information on the diagnosis, treatment, and prevention of genetic and rare disorders; and (3) coordinate with organizations and associations interested in genetic and rare disorders to explore networking capabilities, avoid duplication of effort, and identify information gaps. See:


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Last Reviewed: July 22, 2005