William A Gahl

National Human Genome Research Institute, 베서스다, Maryland, United States

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Publications (490)3397.35 Total impact

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    ABSTRACT: Hermansky-Pudlak syndrome (HPS) comprises a group of inherited disorders caused by mutations that alter the function of lysosome-related organelles. Pulmonary fibrosis is the major cause of morbidity and mortality in patients with subtypes HPS-1 and HPS-4, which both result from defects in biogenesis of lysosome-related organelle complex 3 (BLOC-3). The prototypic chitinase-like protein chitinase 3-like-1 (CHI3L1) plays a protective role in the lung by ameliorating cell death and stimulating fibroproliferative repair. Here, we demonstrated that circulating CHI3L1 levels are higher in HPS patients with pulmonary fibrosis compared with those who remain fibrosis free, and that these levels associate with disease severity. Using murine HPS models, we also determined that these animals have a defect in the ability of CHI3L1 to inhibit epithelial apoptosis but exhibit exaggerated CHI3L1-driven fibroproliferation, which together promote HPS fibrosis. These divergent responses resulted from differences in the trafficking and effector functions of two CHI3L1 receptors. Specifically, the enhanced sensitivity to apoptosis was due to abnormal localization of IL-13Rα2 as a consequence of dysfunctional BLOC-3-dependent membrane trafficking. In contrast, the fibrosis was due to interactions between CHI3L1 and the receptor CRTH2, which trafficked normally in BLOC-3 mutant HPS. These data demonstrate that CHI3L1-dependent pathways exacerbate pulmonary fibrosis and suggest CHI3L1 as a potential biomarker for pulmonary fibrosis progression and severity in HPS.
    The Journal of clinical investigation 06/2015; DOI:10.1172/JCI79792 · 13.77 Impact Factor
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    ABSTRACT: PIGT-CDG, an autosomal recessive syndromic intellectual disability disorder of glycosylphosphatidylinositol (GPI) anchors, was recently described in two independent kindreds [Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 3 (OMIM, #615398)]. PIGT encodes phosphatidylinositol-glycan biosynthesis class T, a subunit of the heteropentameric transamidase complex that facilitates the transfer of GPI to proteins. GPI facilitates attachment (anchoring) of proteins to cell membranes. We describe, at ages 7 and 6years, two children of non-consanguineous parents; they had hypotonia, severe global developmental delay, and intractable seizures along with endocrine, ophthalmologic, skeletal, hearing, and cardiac anomalies. Exome sequencing revealed that both siblings had compound heterozygous variants in PIGT (NM_015937.5), i.e., c.918dupC, a novel duplication leading to a frameshift, and c.1342C>T encoding a previously described missense variant. Flow cytometry studies showed decreased surface expression of GPI-anchored proteins on granulocytes, consistent with findings in previous cases. These siblings further delineate the clinical spectrum of PIGT-CDG, reemphasize the neuro-ophthalmologic presentation, clarify the endocrine features, and add hypermobility, low CSF albumin quotient, and hearing loss to the phenotypic spectrum. Our results emphasize that GPI anchor-related congenital disorders of glycosylation (CDGs) should be considered in subjects with early onset severe seizure disorders and dysmorphic facial features, even in the presence of a normal carbohydrate-deficient transferrin pattern and N-glycan profiling. Currently available screening for CDGs will not reliably detect this family of disorders, and our case reaffirms that the use of flow cytometry and genetic testing is essential for diagnosis in this group of disorders. Copyright © 2015. Published by Elsevier Inc.
    Molecular Genetics and Metabolism 05/2015; 115(2-3). DOI:10.1016/j.ymgme.2015.04.007 · 2.83 Impact Factor
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    ABSTRACT: Intellectual disability (ID) is a heterogeneous condition arising from a variety of environmental and genetic factors. Among these causes are defects in transcriptional regulators. Herein, we report on two brothers in a nonconsanguineous family with novel compound heterozygous, disease-segregating mutations (NM_015979.3: [3656A > G];[4006C > T], NP_057063.2: [H1219R];[R1336X]) in MED23. This gene encodes a subunit of the Mediator complex that modulates the expression of RNA polymerase II-dependent genes. These brothers, who had profound ID, spasticity, congenital heart disease, brain abnormalities, and atypical electroencephalography, represent the first case of MED23-associated ID in a non-consanguineous family. They also expand upon the clinical features previously reported for mutations in this gene. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 04/2015; 167(6). DOI:10.1002/ajmg.a.37047 · 2.05 Impact Factor
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    ABSTRACT: Snyder-Robinson Syndrome (SRS) is an X-linked intellectual disability disorder also characterized by osteoporosis, scoliosis, and dysmorphic facial features. It is caused by mutations in SMS, a ubiquitously expressed gene encoding the polyamine biosynthetic enzyme spermine synthase. We hypothesized that the tissue specificity of SRS arises from differential sensitivity to spermidine toxicity or spermine deficiency. We performed detailed clinical, endocrine, histopathologic, and morphometric studies on two affected brothers with a spermine synthase loss of function mutation (NM_004595.4:c.443A > G, p.Gln148Arg). We also measured spermine and spermidine levels in cultured human bone marrow stromal cells (hBMSCs) and fibroblasts using the Biochrom 30 polyamine protocol and assessed the osteogenic potential of hBMSCs. In addition to the known tissue-specific features of SRS, the propositi manifested retinal pigmentary changes, recurrent episodes of hyper- and hypoglycemia, nephrocalcinosis, renal cysts, and frequent respiratory infections. Bone histopathology and morphometry identified a profound depletion of osteoblasts and osteoclasts, absence of a trabecular meshwork, a low bone volume and a thin cortex. Comparison of cultured fibroblasts from affected and unaffected individuals showed relatively small changes in polyamine content, whereas comparison of cultured osteoblasts identified marked differences in spermidine and spermine content. Osteogenic differentiation of the SRS-derived hBMSCs identified a severe deficiency of calcium phosphate mineralization. Our findings support the hypothesis that cell specific alterations in polyamine metabolism contribute to the tissue specificity of SRS features, and that the low bone density arises from a failure of mineralization.
    Orphanet Journal of Rare Diseases 03/2015; 10(1):27. DOI:10.1186/s13023-015-0235-8 · 3.96 Impact Factor
  • William A. Gahl
    38th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders; 03/2015
  • 38th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders; 03/2015
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    ABSTRACT: In mitochondria, carbamoyl phosphate synthetase 1 activity produces carbamoyl phosphate for urea synthesis, and deficiency results in hyperammonemia. Cytoplasmic carbamoyl phosphate synthetase 2, however, is part of a tri-functional enzyme encoded by CAD; no human disease has been attributed to this gene. The tri-functional enzyme contains carbamoyl-phosphate synthetase 2 (CPS2), aspartate transcarbamylase (ATCase), and dihydroorotase (DHOase) activities, which comprise the first three of six reactions required for de novo pyrimidine biosynthesis. Here we characterize an individual who is compound heterozygous for mutations in different domains of CAD. One mutation, c.1843-1G>A, results in an in-frame deletion of exon thirteen. The other, c.6071G>A, causes a missense mutation (p.Arg2024Gln) in a highly conserved residue that is essential for carbamoyl-phosphate binding. Metabolic flux studies showed impaired aspartate incorporation into RNA and DNA through the de novo synthesis pathway. In addition, CTP, UTP, and nearly all UDP-activated sugars that serve as donors for glycosylation were decreased. Uridine supplementation rescued these abnormalities, suggesting a potential therapy for this new glycosylation disorder. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Human Molecular Genetics 02/2015; 24(11). DOI:10.1093/hmg/ddv057 · 6.68 Impact Factor
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    ABSTRACT: Store-operated Ca2 + entry is the major route of replenishment of intracellular Ca2 + in animal cells in response to depletion of Ca2 + stores in the endoplasmic reticulum. It is primarily mediated by the Ca2 + selective release-activated Ca2 + (CRAC) channel which consists of the pore-forming subunits ORAI1–3 and the Ca2 + sensors, STIM1 and STIM2. Recessive loss-of-function mutations in STIM1 or ORAI1 result in immune deficiency and nonprogressive myopathy. Heterozygous gain-of-function mutations in STIM1 cause non-syndromic myopathies as well as syndromic forms of miosis and myopathy with tubular aggregates and Stormorken syndrome; some of these syndromic forms are associated with thrombocytopenia. Increased concentration of Ca2 + as a result of store-operated Ca2 + entry is essential for platelet activation. York Platelet syndrome (YPS) is characterized by thrombocytopenia, striking ultrastructural platelet abnormalities including giant electron opaque organelles and massive, multi-layered target bodies and deficiency of platelet Ca2 + storage in delta granules. We present clinical and molecular findings in 7 YPS patients from 4 families, demonstrating that YPS patients have a chronic myopathy associated with rimmed vacuoles and heterozygous gain-of-function STIM1 mutations. These findings expand the phenotypic spectrum of STIM1-related human disorders and define the molecular basis of YPS.
    Molecular Genetics and Metabolism 12/2014; 114(3). DOI:10.1016/j.ymgme.2014.12.307 · 2.83 Impact Factor
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    ABSTRACT: Nephropathic cystinosis is a lysosomal storage disorder characterized by renal tubular Fanconi syndrome in infancy and glomerular damage leading to renal failure at ∼10 years of age. Therapy with the cystine-depleting agent cysteamine postpones renal failure, but the degree of compliance with this treatment has not been correlated with preservation of kidney function. We assessed leucocyte cystine depletion by cysteamine and created the composite compliance score that incorporates the extent of leucocyte cystine depletion, as well as duration of cysteamine treatment, into a single integer. Age at renal failure was used to gauge preservation of renal function, and the Fanconi syndrome index (FSI), a measure of aminoaciduria, was used to assess renal tubular Fanconi syndrome. Age at renal failure varied directly and linearly with the composite compliance score (y = 0.3x +8.8; R(2) = 0.61). The slope indicated that for every year of excellent cystine depletion, nearly 1 year of renal function was preserved. Age at renal failure correlated roughly with mean leucocyte cystine level, but not with mean cysteamine dosage. There was no correlation between the FSI and the composite compliance score. Greater compliance with oral cysteamine therapy yields greater preservation of renal glomerular, but not tubular, function. Oral cysteamine therapy should be given at the maximum tolerated dose, within the recommended limits.
    Pediatric Nephrology 12/2014; 30(6). DOI:10.1007/s00467-014-3018-x · 2.88 Impact Factor
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    ABSTRACT: GNE myopathy is a rare autosomal recessive muscle disease caused by mutations in GNE, the gene encoding the rate-limiting enzyme in sialic acid biosynthesis. GNE myopathy usually manifests in early adulthood with distal myopathy that progresses slowly and symmetrically, first involving distal muscles of the lower extremities, followed by proximal muscles with relative sparing of the quadriceps. Upper extremities are typically affected later in the disease. We report a patient with GNE myopathy who presented with asymmetric hand weakness. He had considerably decreased left grip strength, atrophy of the left anterior forearm and fibro-fatty tissue replacement of left forearm flexor muscles on T1-weighted magnetic resonance imaging. The patient was an endoscopist and thus the asymmetric hand involvement may be associated with left hand overuse in daily repetitive pinching and gripping movements, highlighting the possible impact of environmental factors on the progression of genetic muscle conditions.
    Neuromuscular Disorders 12/2014; DOI:10.1016/j.nmd.2014.07.006 · 3.13 Impact Factor
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    ABSTRACT: Hermansky–Pudlak syndrome (HPS) is a genetic disorder characterized by oculocutaneous albinism, bleeding tendency and susceptibility to pulmonary fibrosis. No curative therapy is available. Genetic correction directed to the lungs, bone marrow and/or gastro-intestinal tract might provide alternative forms of treatment for the diseases multi-systemic complications. We demonstrate that lentiviral-mediated gene transfer corrects the expression and function of the HPS1 gene in patient dermal melanocytes, which opens the way to development of gene therapy for HPS.
    Molecular Genetics and Metabolism 11/2014; 114(1). DOI:10.1016/j.ymgme.2014.11.006 · 2.83 Impact Factor
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    ABSTRACT: Mutations in ERCC6 are associated with growth failure, intellectual disability, neurological dysfunction and deterioration, premature aging, and photosensitivity. We describe siblings with biallelic ERCC6 mutations (NM_000124.2:c. [543 + 4delA];[2008C > T]) and brain hypomyelination, microcephaly, cognitive decline, and skill regression but without photosensitivity or progeria. DNA repair assays on cultured skin fibroblasts confirmed a defect of transcription-coupled nucleotide excision repair and increased ultraviolet light sensitivity. This report expands the disease spectrum associated with ERCC6 mutations. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 11/2014; 164A(11). DOI:10.1002/ajmg.a.36709 · 2.05 Impact Factor
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    ABSTRACT: The rate of progression of most interstitial lung diseases is unpredictable. Fibrocytes are circulating bone marrow-derived cells that have been implicated in the pathogenesis of lung fibrosis. Hermansky-Pudlak syndrome, a genetic cause of interstitial lung disease in early adulthood, allows for study of biomarkers of interstitial lung disease in a homogeneous population at near certain risk of developing fibrotic lung disease.
    American Journal of Respiratory and Critical Care Medicine 10/2014; DOI:10.1164/rccm.201407-1287OC · 11.99 Impact Factor
  • 43rd Annual Meeting of the Child-Neurology-Society; 10/2014
  • 19th International Congress of the World-Muscle-Society; 10/2014
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    ABSTRACT: Purpose Autosomal recessive polycystic kidney disease (ARPKD) is the most common childhood-onset ciliopathy. As treatments improve, more women are reaching reproductive age, but little is known about ARPKD and pregnancy. Methods In our ongoing study on ARPKD and other ciliopathies, 12 females over 18 years of age were identified and systematically evaluated. Six had children; four carried pregnancies and delivered, one used assisted reproductive technology and had a surrogate carry the pregnancy, and one adopted. We report the outcomes of four pregnancies with live birth deliveries and two women who chose alternate family building options. Results Patient one was diagnosed at 6 months, and at age 21 had a pregnancy complicated by transient worsening of renal function (creatinine increase from 1.15 to 1.78 mg/dL). Patient two was diagnosed with ARPKD at age seven and had an uncomplicated pregnancy at age 23. Patient three was diagnosed incidentally with ARPKD at age 23, 3 months after completion of an uncomplicated pregnancy. Patient four who had an uncomplicated pregnancy at age 33 was diagnosed with ARPKD at age 46. Conclusions Women with ARPKD face reproductive decisions largely bereft of information about the pregnancies of other ARPKD patients. We report four cases of pregnancy and ARPKD to expand current knowledge and encourage further research.
    Archives of Gynecology and Obstetrics 09/2014; 291(3). DOI:10.1007/s00404-014-3445-8 · 1.28 Impact Factor
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    ABSTRACT: Cystinosis is caused by mutations in the CTNS gene (17p13.2), which encodes for a lysosomal cystine/proton symporter termed cystinosin. It is the most common cause of inherited renal Fanconi syndrome in young children. Because of its rarity, the diagnosis and specific treatment of cystinosis are frequently delayed, which has a significant impact on the overall prognosis. In this document, we have summarized expert opinions on several aspects of the disease to improve knowledge and provide guidance for diagnosis and treatment.
    Nephrology Dialysis Transplantation 09/2014; 29(suppl 4):iv87-iv94. DOI:10.1093/ndt/gfu090 · 3.49 Impact Factor
  • Anne R Pariser, William A Gahl
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    ABSTRACT: Rare diseases play a leading role in innovation and the advancement of medical and pharmaceutical science. Most rare diseases are genetic disorders or atypical manifestations of infectious, immunologic, or oncologic diseases; they all provide opportunities to study extremes of human pathology and provide insight into both normal and aberrant physiology. Recently, drug development has become increasingly focused on classifying diseases largely on genetic grounds; this has allowed the identification of molecularly defined targets and the development of targeted therapies. Clinical trials are now focusing on progressively smaller subgroups within both common and rare disease populations, often based on genetic tests or biomarkers. Drug developers, researchers, and regulatory agencies face a variety of challenges throughout the life cycle of drug research and development for rare diseases. These include the small numbers of patients available for study, lack of knowledge of the disease's natural history, incomplete understanding of the basic mechanisms causing the disorder, and variability in disease severity, expression, and course. Traditional approaches to rare disease clinical research have not kept pace with advances in basic science, and increased attention to translational science is needed to address these challenges, especially diagnostic testing, registries, and novel trial designs.
    Journal of General Internal Medicine 07/2014; DOI:10.1007/s11606-014-2881-2 · 3.42 Impact Factor
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    ABSTRACT: Aim: The exact pathomechanism of GNE myopathy remains elusive, but likely involves aberrant sialylation. We explored sialylation status of blood-based glycans as potential disease markers. Methods: We employed immunoblotting, lectin histochemistry and mass spectrometry. Results: GNE myopathy muscle showed hyposialylation of predominantly O-linked glycans. The O-linked glycome of patients' plasma compared with controls showed increased amounts of desialylated Thomsen-Friedenreich (T)-antigen, and/or decreased amounts of its sialylated form, ST-antigen. Importantly, all patients had increased T/ST ratios compared with controls. These ratios were normalized in a patient treated with intravenous immunoglobulins as a source of sialic acid. Discussion: GNE myopathy clinical trial data will reveal whether T/ST ratios correlate to muscle function. Conclusion: Plasma T/ST ratios are a robust blood-based biomarker for GNE myopathy, and may also help explain the pathology and course of the disease.
    Biomarkers in Medicine 06/2014; 8(5):641-52. DOI:10.2217/bmm.14.2 · 2.86 Impact Factor
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    ABSTRACT: Objective Hereditary spastic paraplegias (HSPs) are among the most genetically diverse inherited neurological disorders, with over 70 disease loci identified (SPG1-71) to date. SPG15 and SPG11 are clinically similar, autosomal recessive disorders characterized by progressive spastic paraplegia along with thin corpus callosum, white matter abnormalities, cognitive impairment, and ophthalmologic abnormalities. Furthermore, both have been linked to early-onset parkinsonism.Methods We describe two new cases of SPG15 and investigate cellular changes in SPG15 and SPG11 patient-derived fibroblasts, seeking to identify shared pathogenic themes. Cells were evaluated for any abnormalities in cell division, DNA repair, endoplasmic reticulum, endosomes, and lysosomes.ResultsFibroblasts prepared from patients with SPG15 have selective enlargement of LAMP1-positive structures, and they consistently exhibited abnormal lysosomal storage by electron microscopy. A similar enlargement of LAMP1-positive structures was also observed in cells from multiple SPG11 patients, though prominent abnormal lysosomal storage was not evident. The stabilities of the SPG15 protein spastizin/ZFYVE26 and the SPG11 protein spatacsin were interdependent.InterpretationEmerging studies implicating these two proteins in interactions with the late endosomal/lysosomal adaptor protein complex AP-5 are consistent with shared abnormalities in lysosomes, supporting a converging mechanism for these two disorders. Recent work with Zfyve26−/− mice revealed a similar phenotype to human SPG15, and cells in these mice had endolysosomal abnormalities. SPG15 and SPG11 are particularly notable among HSPs because they can also present with juvenile parkinsonism, and this lysosomal trafficking or storage defect may be relevant for other forms of parkinsonism associated with lysosomal dysfunction.
    06/2014; 1(6). DOI:10.1002/acn3.64

Publication Stats

11k Citations
3,397.35 Total Impact Points


  • 2002–2015
    • National Human Genome Research Institute
      베서스다, Maryland, United States
  • 1986–2014
    • National Institutes of Health
      • • Office of Rare Diseases Research
      • • Rehabilitation Medicine Department
      • • Cell Biology and Metabolism Program
      • • Branch of Dermatology
      • • Section on Human Genetics
      • • Branch of Genetics
      Maryland, United States
  • 2013
    • BC Children's Hospital
      Vancouver, British Columbia, Canada
  • 2001–2013
    • Northern Inyo Hospital
      BIH, California, United States
  • 2010
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States
  • 2005–2009
    • Great Ormond Street Hospital for Children NHS Foundation Trust
      Londinium, England, United Kingdom
    • Sheba Medical Center
      Gan, Tel Aviv, Israel
    • Dartmouth–Hitchcock Medical Center
      Lebanon, New Hampshire, United States
  • 1988–2009
    • National Eye Institute
      베서스다, Maryland, United States
    • University of Helsinki
      Helsinki, Uusimaa, Finland
    • The Ohio State University
      • Department of Obstetrics and Gynecology
      Columbus, OH, United States
    • IT University of Copenhagen
      København, Capital Region, Denmark
  • 2007
    • University of Nice-Sophia Antipolis
      Nice, Provence-Alpes-Côte d'Azur, France
  • 2006
    • George Washington University
      Washington, Washington, D.C., United States
  • 2003
    • Brown University
      Providence, Rhode Island, United States
  • 1982–2003
    • National Institute of Child Health and Human Development
      Maryland, United States
  • 2000
    • National Heart, Lung, and Blood Institute
      Maryland, United States
  • 1995–1999
    • Eunice Kennedy Shriver National Institute of Child Health and Human Development
      Роквилл, Maryland, United States
    • University of Oslo
      Kristiania (historical), Oslo County, Norway
    • Virginia Commonwealth University
      • Department of Pediatrics
      Ричмонд, Virginia, United States
  • 1994
    • Tokyo Medical and Dental University
      • Department of Biochemical Genetics
      Edo, Tōkyō, Japan
  • 1993
    • Thomas Jefferson University
      Filadelfia, Pennsylvania, United States
    • National Institute on Aging
      • Laboratory of Neurosciences (LNS)
      Baltimore, Maryland, United States
  • 1989–1991
    • Johns Hopkins University
      • • Department of Pathology
      • • Department of Pediatrics
      Baltimore, MD, United States
  • 1984–1991
    • University of California, San Diego
      • • Department of Pediatrics
      • • Department of Medicine
      San Diego, California, United States
  • 1990
    • The National Institute of Diabetes and Digestive and Kidney Diseases
      베서스다, Maryland, United States
  • 1987–1988
    • Johns Hopkins Medicine
      Baltimore, Maryland, United States
    • Wayne State University
      Detroit, Michigan, United States
    • NEI Corporation
      Сомерсет, New Jersey, United States
    • Radboud University Nijmegen
      Nymegen, Gelderland, Netherlands
  • 1978–1982
    • University of Wisconsin–Madison
      • • Department of Statistics
      • • Department of Pediatrics
      Madison, Wisconsin, United States