Ubiquitin ligases play an important role in the regulation of the immune system. Absence of Itch E3 ubiquitin ligase in mice has been shown to cause severe autoimmune disease. Using autozygosity mapping in a large Amish kindred, we identified a linkage region on chromosome 20 and selected candidate genes for screening. We describe, in ten patients, identification of a mutation resulting in truncation of ITCH. These patients represent the first reported human phenotype associated with ITCH deficiency. These patients not only have multisystem autoimmune disease but also display morphologic and developmental abnormalities. This disorder underscores the importance of ITCH ubiquitin ligase in many cellular processes.
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- Clinical Case Report
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Published Papers
The primary goal of our research will always be to find effective and affordable treatments for patients. One of the central focus areas of our mission is sharing our methods and discoveries with the broader scientific community.
In the over 35 years since the Clinic's founding, our staff have published more than 130 peer-reviewed research papers, fueled by close collaboration between our clinical and laboratory teams and effective relationships with academic, scientific, and clinical partners.
Authors: Xin B, Puffenberger EG, Turben S, Tan H, Zhou A, Wang H
We identified an autosomal recessive condition in 11 individuals in the Old Order Amish of northeastern Ohio. The syndrome was characterized by distinctive craniofacial dysmorphism, skeletal anomalies, and mental retardation. The typical craniofacial dysmorphism included brachycephaly, highly arched bushy eyebrows, synophrys, long eyelashes, low-set ears, microdontism of primary teeth, and generalized gingival hyperplasia, whereas Sprengel deformity of scapula, fusion of spine, rib abnormities, pectus excavatum, and pes planus represented skeletal anomalies. The genome-wide homozygosity mapping using six affected individuals localized the disease gene to a 3.3-Mb region on chromosome 1q23.3-q24.1. Candidate gene sequencing identified a homozygous frameshift mutation, c.139_140delAG, in the transmembrane and coiled-coil domains 1 (TMCO1) gene, as the pathogenic change in all affected members of the extended pedigree. This mutation is predicted to result in a severely truncated protein (p.Ser47Ter) of only one-fourth the original length. The TMCO1 gene product is a member of DUF841 superfamily of several eukaryotic proteins with unknown function. The gene has highly conserved amino acid sequence and is universally expressed in all human tissues examined. The high degree of conservation and the ubiquitous expression pattern in human adult and fetal tissues suggest a critical role for TMCO1. This report shows a TMCO1 sequence variant being associated with a genetic disorder in human. We propose “TMCO1 defect syndrome” as the name of this condition.
Authors: Strauss KA, Donnelly P, Wintermark M
In glutaric aciduria type 1, glutaryl-coenzyme A and its derivatives are produced from intracerebral lysine and entrapped at high concentrations within the brain, where they interfere with energy metabolism. Biochemical toxicity is thought to trigger stroke-like striatal degeneration in susceptible children under 2 years of age. Here, we explore vascular derangements that might also contribute to brain damage. We studied injured and non-injured Amish glutaric aciduria type 1 patients using magnetic resonance imaging (n = 26), transcranial Doppler ultrasound (n = 35) and perfusion computed tomography (n = 6). All glutaric aciduria type 1 patients had wide middle cerebral, internal carotid and basilar arteries. In non-injured patients, middle cerebral artery velocities were 18-26% below control values throughout late infancy and early childhood, whereas brain-injured children had an early velocity peak (18 months) and low values thereafter. Perfusion scans from six patients showed that tissue blood flow did not undergo a normal developmental surge. We observed four different perfusion patterns. (i) Three children (two non-injured) had low cerebral blood flow, prolonged mean transit time, elevated cerebral blood volume and high mean transit time/cerebral blood flow and cerebral blood volume/cerebral blood flow ratios. This pattern optimizes substrate extraction at any given flow rate but indicates low perfusion pressure and limited autoregulatory reserve. (ii) Ten hours after the onset of striatal necrosis in an 8-month-old infant, mean transit time and cerebral blood volume were low relative to cerebral blood flow, which varied markedly from region to region. This pattern indicates disturbed autoregulation, regional perfusion pressure gradients, or redistribution of flow from functional capillaries to non-exchanging vessels. (iii) In an infant with atrophic putaminal lesions, striatal flow was normal but mean transit time and cerebral blood volume were low, consistent with perfusion in excess of metabolic demand. (iv) Finally, a brain-injured adult with glutaric aciduria type 1 had regional perfusion values within the normal range, but the putamina, which normally have the highest regional perfusion, had cerebral blood flow values 24% below cortical grey matter. Although metabolic toxicity appears central to the pathophysiology of striatal necrosis, cerebrovascular changes probably also contribute to the process. These changes may be the primary cause of expanded cerebrospinal fluid volume in newborns, intracranial and retinal haemorrhages in infants and interstitial white matter oedema in children and adults. This pilot study suggests important new areas for clinical investigation.
Authors: Biery BJ, Stein DE, Morton DH, Goodman SI
The structure of the human glutaryl coenzyme A dehydrogenase (GCD) gene was determined to contain 11 exons and to span approximately 7 kb. Fibroblast DNA from 64 unrelated glutaric acidemia type I (GA1) patients was screened for mutations by PCR amplification and analysis of SSCP. Fragments with altered electrophoretic mobility were subcloned and sequenced to detect mutations that caused GA1. This report describes the structure of the GCD gene, as well as point mutations and polymorphisms found in 7 of its 11 exons. Several mutations were found in more than one patient, but no one prevalent mutation was detected in the general population. As expected from pedigree analysis, a single mutant allele causes GA1 in the Old Order Amish of Lancaster County, Pennsylvania. Several mutations have been expressed in Escherichia coli, and all produce diminished enzyme activity. Reduced activity in GCD encoded by the A421V mutation in the Amish may be due to impaired association of enzyme subunits.
Authors: Strauss KA, Puffenberger EG
The Old Order Amish and Old Order Mennonite populations of Pennsylvania are descended from Swiss Anabaptist immigrants who came to the New World in the early eighteenth century. Today they live in many small endogamous demes across North America. Genetically, these demes have dissimilar allele frequencies and disease spectra owing to unique founders. Biological and social aspects of Old Order communities make them ideal for studies in population genetics and genomic medicine, and over the last 40 years, advances in genomic science coincided with investigational studies in Plain populations. Newer molecular genetic technologies are sufficiently informative, rapid, and flexible to use in a clinical setting, and we have successfully integrated these tools into a rural pediatric practice. Our studies with the Pennsylvania Plain communities show that population-specific genetic knowledge provides a powerful framework in which to prevent disease, reduce medical costs, and create new insights into human biology.
Authors: Rider NL, Morton DH, Puffenberger E, Hendrickson CL, Robinson DL, Strauss KA
Cartilage-hair hypoplasia is a short limbed skeletal dysplasia associated with impairments in host-defense. To better understand the clinical heterogeneity of this disorder, we studied 25 Amish patients with homozygous mutations in RMRP (RMRP 70 A>G). Despite mutation homogeneity, eight (32%) patients had severe or recurrent infections, two (8%) of these children underwent bone-marrow transplantation for combined immunodeficiency, and the remainder were healthy. Features distinguishing patients who underwent bone marrow transplantation from others were shorter birth length, and lower serum IgG, undetectable serum IgA, and elevated circulating NK cells before 2 years of age. Irrespective of clinical phenotype, most patients had lymphopenia and reduced lymphocyte proliferation to mitogens in vitro. Our cohort analysis suggests that many patients with cartilage-hair hypoplasia are at risk for infection susceptibility particularly during the first 2 years of life. Gauging this risk is difficult, and thus careful monitoring of all patients with cartilage-hair hypoplasia is warranted.
Authors: Lahiry P, Wang J, Robinson JF, Turowec JP, Litchfield DW, Lanktree MB, Gloor GB, Puffenberger EG, Strauss KA, Martens MB, Ramsay DA, Rupar CA, Siu V, Hegele RA
Six infants in an Old Order Amish pedigree were observed to be affected with endocrine-cerebro-osteodysplasia (ECO). ECO is a previously unidentified neonatal lethal recessive disorder with multiple anomalies involving the endocrine, cerebral, and skeletal systems. Autozygosity mapping and sequencing identified a previously unknown missense mutation, R272Q, in ICK, encoding intestinal cell kinase (ICK). Our results established that R272 is conserved across species and among ethnicities, and three-dimensional analysis of the protein structure suggests protein instability due to the R272Q mutation. We also demonstrate that the R272Q mutant fails to localize at the nucleus and has diminished kinase activity. These findings suggest that ICK plays a key role in the development of multiple organ systems.
Authors: Jakubowski H, Boers GH, Strauss KA
Severely elevated plasma homocysteine(Hcy) levels observed in genetic disorders of Hcymetabolism are associated with pathologies in multipleorgans and lead to premature death due to vascularcomplications. In addition to elevating plasma Hcy,mutations in cystathionine -synthase (CBS) or methyl-enetetrahydrofolate reductase (MTHFR) gene lead tomarkedly elevated levels of circulating Hcy-thiolactone.The thiooester chemistry of Hcy-thiolactone underliesits ability to form isopeptide bonds with protein lysineresidues (N-Hcy-protein), which may impair or alter theprotein’s function. However, it was not known whethergenetic deficiencies in Hcy metabolism affect N-Hcy-protein levels in humans. Here we show that plasmaN-Hcy-protein levels are significantly elevated in CBS-and MTHFR-deficient patients. We also show that CBS-deficient patients have significantly elevated plasma levelsof prothrombotic N-Hcy-fibrinogen. These results pro-vide a possible explanation for increased atherothrombo-sis observed in CBS-deficient patients.
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Our clinic serves as a trusted medical practice for children and adults facing rare genetic disorders. Our dedicated team works every day to prevent and treat genetic illnesses. Our facility is in the heart of the Amish and Mennonite communities in Lancaster County. Inside is filled with cutting-edge gene sequencing tools that allow us to deliver highly personalized care—a precise treatment option for the right patient at the right time.