National Human Genome Research Institute (NHGRI)

Overview of NHGRI Rare Diseases Research Activities

NHGRI has the responsibility at NIH for providing leadership and support for the Human Genome Project (HGP) and for conducting a vigorous research program aimed at understanding and treating both simple and complex genetic disorders.

HGP is an international collaboration to characterize the complete set of genetic instructions encoded in the estimated 3 billion base pairs of DNA. Since October 1990, HGP has been funded in the United States by NHGRI and the Department of Energy (DOE). International partners include the United Kingdom, France, Germany, Japan, and China. A major goal of HGP is to read each of the 3 billion bases, or letters, in the human genetic instruction book. The rapid availability of sequence, deposited every 24 hours into publicly available databases, is providing valuable information to the research community.

Using the information and tools produced by HGP, scientists in the Institute's intramural research program are developing techniques to study the fundamental mechanisms of genetic disorders and genetic factors involved in common diseases. These cutting-edge approaches are yielding new knowledge about human genetic diseases and their diagnosis, prevention, and treatment.

Recent Scientific Advances in Rare Diseases Research

Tools for Gene Discovery

Human DNA Sequencing

Diseases are know to tend to run in families. In fact, nearly all diseases have a genetic component, including such common diseases as diabetes, schizophrenia, and cancer. HGP aims to understand the mysteries of disease by unraveling the secrets of the 3 billion bits of information in the DNA instruction book present in nearly every cell in our body. The genetic code within DNA holds many potential insights for human susceptibilities and resistances to disease and for the discovery of novel preventive and therapeutic strategies.

In 1999, HGP launched full-scale production sequencing of the human genome. A working draft of 90% of the human genome has been essentially completed. The highly accurate finished product, in which gaps are closed and ambiguities resolved, is expected no later than 2003, 2 years ahead of schedule. All of the DNA sequence is deposited by the publicly supported sequencing centers daily and is available without restriction to any researcher with an Internet connection through the public database, GenBank. The rapid and unfettered availability of the human DNA sequence already has accelerated the isolation of the genes associated with many rare genetic disorders. This in turn is providing clues to researchers to advance the understanding, diagnosis, prevention, and treatment of rare and genetic disorders.

Human DNA sequencing is not the only goal of HGP. The new 5-year HGP Research Plan, published in the journal Science in October 1998, includes another seven ambitious goals. These goals are guiding the development of a new and more diverse set of genomic research tools for researchers in both the public and private sectors to advance our understanding and treatment of human disease. These tools include:

1. Optimization of current sequencing technologies and development of novel strategies.
2. A catalog of common variations, or single-nucleotide polymorphisms (SNPs), in the human DNA sequence.
3. New technologies and strategies for studying the function of genes and genomes.
4. Completion of the DNA mapping and sequence of additional model organisms including the mouse.
5. New approaches to addressing the ethical, legal, and social implications (ELSI) of research.
6. Development of improved databases and analytical tools in bioinformatics and computational biology.
7. Training programs in scientific and ELSI aspects of genomic and genetic sciences. Achievement of these additional HGP goals will greatly assist researchers in understanding human disease at its most fundamental level. It will also enable the development of novel strategies to improve the prevention, diagnosis, and treatment of both common and rare diseases.

Microarray Technology

Microarray technology is one of several approaches being developed to compare gene activity in people with and without a disorder. This technology will benefit rare diseases research, because it can identify altered patterns of gene expression. The Microarray Project is a collaborative research effort headed by NHGRI intramural scientists involving interactions between intramural scientists in NHGRI, NCBI, NINDS, and NIMH. The ultimate goal of the Microarray Project is to develop arrays that can track the activity of every gene in the genome.

"Tissue Chip" Microarrays

NHGRI scientists, in collaboration with researchers in Finland and Switzerland, have developed a research tool called the tissue chip that will eventually help clinicians design individual treatment plans. Scientists can use this tool to analyze the genetic material and protein in tissue biopsies and compare them to both normal tissue and to tissue from people with known diseases. As many as 1,000 biopsies can be analyzed in a single tumor tissue array the size of a postage stamp. When fully developed, this tool will allow clinicians to make rapid diagnoses of even rare disorders and to better predict how a given patient will respond to available treatments and medications.

Genetics of Human Diseases

Scientists in NHGRI's Division of Intramural Research (DIR) apply genomic tools to the study of human genetic diseases, many of which are rare. In 1999, research progress took place in several areas.

Disorders of the Immune System

Severe Combined Immunodeficiency (SCID). NHGRI scientists are using immunology, genetics, molecular biology, and gene therapy to study and treat inherited and acquired immunodeficiency diseases. Areas of emphasis include adenosine deaminase SCID, X-linked SCID (the most common of the several genetic defects causing the SCID syndrome), Wiskott-Aldrich syndrome, and JAK3 (Janus kinase 3) deficiency.

NHGRI scientists recently identified a gene associated with X-linked severe combined immunodeficiency (X-SCID) and established that it is the major genetic form of human SCID. Investigators also developed methods for mutation detection and prenatal and carrier diagnosis of this form of X-SCID and are investigating the range of naturally occurring mutations and their effects on functional abilities of X-SCID children.

In addition, NHGRI scientists are developing preclinical models of gene therapy for X-SCID, JAK3-SCID, Wiskott-Aldrich syndrome, and others. NHGRI researchers have demonstrated in cell cultures that genetic correction of patient cells leads to restoration of JAK3 function and are now performing stem cell gene transfer experiments in a mouse model to assess safety and efficacy issues and to identify the ideal gene transfer vehicle to be selected for future clinical applications. NHGRI intramural scientists also are developing a clinical protocol for gene therapy of ADA deficiency in collaboration with investigators at the Children's Hospital Los Angeles.

Job's Syndrome (Hyper-IgE Syndrome). Job's syndrome (after the biblical character who was smitten with boils), or hyper-IgE syndrome, is a rare and puzzling immunodeficiency. NHGRI scientists have demonstrated that it is a multisystem disorder that can be inherited as an autosomal dominant trait with variable expressivity. They also have shown that in approximately 50% of families with this disorder, the gene responsible for disease is located on the long arm of chromosome 4. Scientists are now refining this region, searching for disease gene candidates, and conducting searches for additional regions associated with this disorder, as well as launching efforts to understand the nature of the bone fragility and dental abnormalities that are part of the syndrome.

Autoimmune Lymphoproliferative Syndrome. Autoimmune lymphoproliferative syndrome (ALPS) is a recently recognized rare diseases in which a genetic defect in programmed cell death, or apoptosis, leads to breakdown of lymphocyte regulation. Patients with ALPS have chronic enlargement of the spleen and lymph nodes, various manifestations of autoimmunity, and elevation of a normally rare population of double-negative (CD4 CD8 ) cells due to mutations in the gene encoding FAS, a cell surface apoptosis receptor. Researchers are investigating the spectrum of cellular abnormalities in this syndrome, as well as the relationship between mutations in FAS pathway genes and clinical manifestations.

Familial Mediterranean Fever. Since its discovery in 1997 by NIAMS and NHGRI scientists, many different alterations have been identified in the gene responsible for familial Mediterranean fever (FMF), a disease characterized by periodic attacks of fever, elevated neutrophils in the circulation, and abdominal pain. The function of the protein made by this gene is still unclear, though it is likely to play an important role in inflammatory and immune responses. Investigators are studying this protein by examining the features of mice with either deletions or alterations in the FMF gene.

Ducan's Disease/X-Linked Lymphoproliferative Disease. Ducan's disease, or X-linked lymphoproliferative disease (XLP), is a rare human disorder characterized by a fatal lymphoproliferative syndrome that generally develops after exposure to Epstein-Barr virus early in life. Most patients die in early childhood because of massive hepatic and bone marrow infiltration by activated CD8 T cells. Most survivors subsequently develop malignant lymphomas. Nonetheless, the mechanism of this lymphoproliferation is still unclear. The gene responsible for XLP, known as SAP, was cloned last year by several groups. As part of the studies of T-cell activation, researchers have generated a mouse containing a mutation in SAP. They are currently studying T-cell activation and responses to infectious disease models in these mice.

Disorders of the Nervous System

Niemann-Pick Type C. Niemann-Pick type C (NPC) is an autosomal recessive disorder in which patients show neurological decline due to an irregularity in the way the body stores lipid, a type of fat normally found in cell membranes. NHGRI and NINDS scientists cloned the gene responsible for this disease (NPC1) and identified a mouse containing a null mutation in this same gene. Researchers now are generating transgenic animals that introduce the NPC1 gene into specific cells of NPC1 mutant mice. These experiments will determine which cells are needed for correction of the NPC1 phenotypes and will help in potential therapeutic strategies.

Parkinson's Disease. In 1997, investigators at NHGRI identified the first gene to be associated with some cases of familial PD. That gene encodes a protein called -synuclein. Researchers are currently studying the function of this protein by examining mice that do not produce it, as well as mice producing normal or altered forms of the protein. In 1998, NHGRI scientists identified another gene alteration associated with PD. The gene codes for a protein that tags other proteins for routine disposal in the brain.

This finding bolsters their hypothesis that defects in a pathway for disposing of flawed proteins are responsible not only for PD, but also for several other late-onset neurodegenerative disorders such as Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease).

Huntington's Disease. In a specific area of the normal HD gene, three nucleotides repeat anywhere from 11 to 34 times. When there are 40 or more repeats, the individual will develop Huntington's disease, a fatal, autosomal dominant neurological illness causing involuntary movements, severe emotional disturbance, and cognitive decline. Scientists are studying the effect of these extra copies of genetic material by examining the protein they encode. They are also examining mice with varying numbers of repeats to correlate repeat size with manifestations of the disease. Researchers developed a mouse model of Huntington's disease that displays the same brain abnormalities and behavioral and motor problems seen in people with the illness. Studying these mice will allow scientists to monitor the downstream effects of the altered gene, identify potential modifying factors, and evaluate the efficacy of therapeutic approaches toward the management and cure of the disease.

Waardenburg Syndrome and Hirschsprung Disease. Waardenburg syndrome and Hirschsprung disease disrupt the development of specific lineages of neural crest derivatives. NHGRI scientists cloned a gene (SOX10) that is mutated in subsets of individuals with these diseases. They are now using a combination of embryology, transgenics, and microarray analysis to understand the role of this gene in normal neural crest development. This information is used to determine how alterations in this gene result in these diseases. Computational structural analysis is also being done to better understand the effect of point mutations and deletions on the three-dimensional structure of the SOX10 protein.

Congenital Disorders of Glycosylation. This varied group of disorders (formerly called carbohydrate-deficient glycoprotein syndromes) appears in infants as a failure to thrive, problems with multiple organ systems, and severe neurological manifestations. These symptoms are caused by a defect in the body's ability to make N-linked oligosaccharides, sugars important to the normal functioning of the body. American congenital disorders of glycosylation (CDG) patients have both previously reported and newly discovered changes in one enzyme that leads to this disease. The gene for this enzyme, its surrounding DNA, and the differences within the American CDG population are being studied. Biochemical studies are being performed on skin cells and immune cells of two American Type 4 CDG patients. Affected children and adults are being clinically evaluated at the NIH Clinical Center to study the natural history and heterogeneity of these disorders. Ultimately, the observed clinical manifestations, coupled with a better understanding of the molecular basis of disease, will elucidate better diagnostic and therapeutic approaches.

Smith-Magenis Syndrome. Smith-Magenis syndrome (SMS) is characterized by a specific pattern of physical, behavioral, and developmental features. This disease, resulting from a deletion on the short arm of chromosome 17, has been found in more than 200 individuals worldwide representing a diversity of ethnic backgrounds. SMS is rare, although the exact incidence is unknown. Despite improved diagnostic techniques, the diagnosis of SMS is often delayed until early school age; therefore, defining the infant phenotype of SMS to promote early diagnosis is a priority. NHGRI scientists have found physiological explanations for the impairment in voice and speech and have suggested the involvement of a gene important to the development of certain critical structures of voice and speech. Researchers are continuing to study the natural history and pathophysiology of SMS across the lifespan.

Holoprosencephaly. NHGRI researchers are studying holoprosencephaly (HPE), a common structural disorder of the developing forebrain and midface associated with various chromosomal anomalies. Recently, alterations in the human sonic hedgehog (SHH) gene were shown to cause some forms of HPE. Furthermore, irregularities in the ability to make cholesterol were found in a genetic syndrome associated with HPE. Other, yet unidentified HPE-causing genes are thought to be part of the SHH signaling pathway or are involved in the making of cholesterol. A gene for one key enzyme maps to a region of DNA known to be deleted in some HPE patients. NHGRI researchers have determined the entire sequence of this gene, the lanosterol synthase (LS) gene, and have devised a screening strategy to look for mutations in the gene that could be responsible for human disease. Four other genes are also being studied for their possible involvement in HPE. Analysis of regulation, interaction, and physiological role of these genes will help our understanding of normal and abnormal formation of the CNS.

Lowe's Oculocerebrorenal Syndrome. Lowe's oculocerebrorenal syndrome (OCRL) is an X-linked disorder characterized by mental retardation, congenital cataracts, renal tubular dysfunction in childhood, and progressive renal failure in adulthood. NHGRI researchers identified the gene responsible for this disorder (ocrl1). It is an enzyme that is involved in protein trafficking, cytoskeleton polymerization, and intracellular signaling. Scientists are studying cellular and mouse models to understand how deficiencies in this enzyme can lead to the triad of mental retardation, cataracts, and renal tubular dysfunction.

Batten Disease. Juvenile neuronal ceroid lipofuscinosis (NCL type III), known as Batten disease, is a degenerative neurological disease resulting from a lysosomal storage disorder. The gene for Batten disease was identified by a European consortium led by Hannah Mitchison from University College, London. The Batten gene, CLN3, encodes a protein whose function is not really known. In collaboration with Mitchison, scientists at the NHGRI created a knockout mouse model that develops all the histological and biochemical abnormalities seen in Batten disease. Observations in the mouse have led to the development of a possible therapy for Batten disease. The therapeutic trial in mice uses a drug that aims to overcome the lysosomal storage defect by raising the lysosomal pH.

Cobalamin Metabolism. NHGRI researchers have identified the gene responsible for one of the inherited defects of cobalamin metabolism (cobalamin is a form of vitamin B12). This gene, methionine synthase (MS), is altered in individuals carrying the cbl-G form of this disease. Affected individuals exhibit mental retardation and neurological and developmental problems in the first years of life. Scientists also have cloned the mouse version of the MS gene and established a colony of mice with an altered MS gene that serves as a model for the human disease.

Disorders of Connective Tissue

The heritable disorders of connective tissue are a heterogeneous group of conditions affecting multiple organ systems, including the skeleton, skin, and blood vessels.

Human Skeletal Dysplasias. NHGRI investigators are working to identify genes causing a variety of human skeletal dysplasias, including pycnodysostosis, cartilage-hair hypoplasia (CHH), proximal symphalangism, brachydactyly type C, and the type II collagen disorders (such as Stickler syndrome). They are also working to correlate specific genetic alterations with specific clinical features of these diseases. In the past year, the gene for proximal symphalangism has been identified as the Noggin gene on chromosome 17, and the Ellis van Creveld (EvC) gene has been identified on chromosome 4. The Skeletal Genome Anatomy Project (SGAP) has sequenced 6,000 expressed sequence tags (ESTs) to date, resulting in the identification of more than 60 novel sequences expressed in skeletal tissue.

Achondroplasia and Other FGFR3 Disorders. NHGRI scientists are performing clinical and molecular studies of achondroplasia to identify and characterize the causes of illness and death that result from alterations in the fibroblast growth factor receptor 3 (FGFR3) gene. Scientists seek to understand the correlation between symptoms and gene alterations that cause this and other FGFR3-related disorders. A newly identified skeletal dysplasia, with severe achondroplasia, developmental delay, and acanthosis nigricans (SADDAN), has been found to result from a specific FGFR3 mutation. Efforts are under way to further define the clinical phenotype and elucidate the downstream effects of the mutation in the gene.

An additional project focuses on issues surrounding prenatal genetic testing for achondroplasia. Before prenatal tests become widely available, researchers hope to learn more about the lives of affected individuals and their families and the education and counseling needs of these communities.

Marfan's Syndrome and Related Conditions. NHGRI scientists are studying patients with Marfan's syndrome and related conditions ( MASS phenotype, mitral valve prolapse syndrome, familial aortic dissection), Ehlers-Danlos syndrome, and Stickler syndrome. They have collected clinical data on these patients, including detailed information on skeletal, ocular, and cardiovascular aspects of their diseases. Scientists are analyzing skin biopsies and blood samples in an effort to correlate clinical findings with specific biochemical and genetic alterations. New diagnostic criteria for Marfan's syndrome have been proposed; the clinical findings in this study will be used to assess the validity of these proposed diagnostic criteria. Other research is designed to increase the understanding of the psychological and social needs of adults with Marfan's syndrome. This research attempts to correlate adjustment and health behaviors to individual personality traits and family history of Marfan's syndrome. Last year, researchers distributed a questionnaire to study participants. Investigators received 174 questionnaires back from adults with Marfan's syndrome and are analyzing data on illness perception and adherence to medical recommendations, quality of life and depression, use of social support, sex and reproduction, and insurance and potential discrimination events.

Developmental Disorders and Disorders of Early Childhood

Alagille Syndrome. Alagille syndrome (AGS) is a developmental disorder affecting multiple organ systems including liver, heart, eye, face, and vertebrae. NHGRI scientists identified a gene responsible for AGS in 1997, which encodes a protein important in early development. Work on the biological consequence of a mutation of this and similar genes is under way. Researchers also have identified and characterized two other human genes that encode a similar protein and provide an opportunity to explore their role, if any, in disease.

Cleft Lip and Palate. NHGRI scientists are performing genetic analyses of hereditary oral clefts. They h ave collected clinical information and blood samples from 20 families in Syria who have many members affected with cleft lip and palate. These large families, together with other families currently being studied at the Johns Hopkins University, will be studied to locate genes associated with this condition. Samples are being genotyped at the NIH-supported Center for Inherited Disease Research (CIDR), and collaborative analyses will be conducted on the results.

Cystic Fibrosis. NHGRI investigators continue to work to understand the elements that regulate the function of the gene responsible for CF, and to develop a cell culture model system that will aid researchers in understanding the cellular changes that result from a mutation in the CF gene. The results from this work are likely to enhance understanding of the disease and will potentially contribute to the development of new gene therapy strategies.

Hemophilia. Although hemophilia A and B are clinically similar diseases, they are caused by alterations in different genes. NHGRI researchers are developing gene therapy protocols for both disorders by studying ways to introduce normal copies of the genes into the cells of hemophilia patients. They also hope to understand hemophilia better by studying strains of mice deficient in either factor VIII or factor IX, the blood-clotting proteins that are lacking in these diseases.

Multiple Congenital Anomaly Syndrome. NHGRI scientists have collected more than 200 families with undiagnosed multiple congenital anomaly syndrome. Investigators are applying cutting-edge techniques to detect subtle duplications and deletions in the DNA of individuals with this syndrome. Researchers already have found five chromosomal aberrations that were not detected by other techniques.

Proteus Syndrome. NHGRI scientists are studying Proteus syndrome, a rare sporadic disorder. Although this disorder is very rare (affecting probably fewer than 500 people in the Western world), it is well known, being popularized in the book, play, and movie The Elephant Man. Proteus syndrome is a disorder of mosaic overgrowth that predisposes to tumors and severe vascular and pulmonary problems. Researchers are performing a natural history study of this disorder and are attempting to isolate genes that are misregulated by comparing expression in cells from affected and nonaffected individuals.

Duane's Retraction Syndrome. Duane's retraction syndrome (DRS) is an eye movement disorder characterized by a failure of the 6th cranial nerve to develop normally. NHGRI investigators have studied a large family in which many members inherit this disorder. They have undertaken a search for a gene involved in this disease and found strong evidence that the gene resides in a particular region on chromosome 2. Three of the genes within this region were known to be involved in hindbrain development, but analysis of the coding sequences for these genes was normal or had genetic alterations unlikely to be responsible for the disease. Knowing the gene responsible for DRS may lead to improved understanding of both the disorder and of early cranial nerve development.

Pallister-Hall Syndrome, Greig Cephalopolysyndactyly Syndrome, and Polydactyly. NHGRI investigators are studying three disorders, Pallister-Hall syndrome, Greig cephalopolysyndactyly syndrome (GCPS), and a form of polydactyly, which all result from alterations in a single gene, GL13. The gene product functions as a zinc finger transcription factor and regulates the expression of other genes. These disorders are single-gene human developmental anomaly syndromes that cause birth defects of variable severity and that affect less than 1,000 people in the developed world. Researchers are looking for relationships between the particular genetic alteration and the clinical features and are performing clinical studies to determine the range of severity and overlap among these disorders. In addition they are developing efficient methods of detecting the wide range of mutations in these syndromes.

Rare Disorders in the Amish Community. NHGRI scientists are investigating several rare disorders that are relatively prevalent among the Old Order Amish, primarily of Lancaster County, Pennsylvania. These disorders include the McKusick-Kaufman syndrome, Amish nemaline myopathy, and Amish microcephaly. As far as researchers are aware, these disorders are either extremely rare or nonexistent outside this population isolate, which numbers approximately 80,000 people. These disorders affect fewer than 100 people among the Old Order Amish. Scientists have isolated the McKusick-Kaufman syndrome gene by positional cloning and the Amish nemaline myopathy gene. The gene for Amish microcephaly has been mapped and efforts are continuing to clone the gene.

Cataract and Craniofacial Anomalies Syndrome. In collaboration with investigators at the Johns Hopkins University, NHGRI scientists are studying a family with a rare syndrome involving congenital cataracts and craniofacial anomalies. The researchers are performing genetic analyses on this family to identify a gene associated with this disorder. Initial analysis resulted in the identification of several promising regions of the genome that require further investigation.

Endocrine Disorders

Multiple Endocrine Neoplasia Type 1. In 1997, NHGRI scientists identified the gene responsible for multiple endocrine neoplasia type 1 (MEN1). Studies are under way to identify the function of the gene whose alteration causes this disorder and how its protein product interacts with other components in the cell. To help them study and understand this disease, NHGRI researchers have established a strain of mice that will develop symptoms of MEN1 and are also examining the role of a gene in zebrafish similar to the MEN1 gene.