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Topic: Pathophysiology

Title: APC7 mediates ubiquitin signaling in constitutive heterochromatin in the developing mammalian brain Published: December 22, 2021 Publication: Molecular Cell

Authors: Cole J. Ferguson, Olivia Urso, Tatyana Bodrug, Brandon M. Gassaway, Edmond R. Watson, Jesuraj R. Prabu, Pablo Lara-Gonzalez, Raquel C. Martinez-Chacin, Dennis Y. Wu, Karlla W. Brigatti, Erik G. Puffenberger, Cora M. Taylor, Barbara Haas-Givler, Robert N. Jinks, Kevin A. Strauss, Arshad Desai, Harrison W. Gabel, Steven P. Gygi, Brenda A. Schulman, Nicholas G. Brown, Azad Bonni

Abstract:
Neurodevelopmental cognitive disorders provide insights into mechanisms of human brain development. Here, we report an intellectual disability syndrome caused by the loss of APC7, a core component of the E3 ubiquitin ligase anaphase promoting complex (APC). In mechanistic studies, we uncover a critical role for APC7 during the recruitment and ubiquitination of APC substrates. In proteomics analyses of the brain from mice harboring the patient-specific APC7 mutation, we identify the chromatin-associated protein Ki-67 as an APC7-dependent substrate of the APC in neurons. Conditional knockout of the APC coactivator protein Cdh1, but not Cdc20, leads to the accumulation of Ki-67 protein in neurons in vivo, suggesting that APC7 is required for the function of Cdh1-APC in the brain. Deregulated neuronal Ki-67 upon APC7 loss localizes predominantly to constitutive heterochromatin. Our findings define an essential function for APC7 and Cdh1-APC in neuronal heterochromatin regulation, with implications for understanding human brain development and disease.
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Title: A biallelic SNIP1 Amish founder variant causes a recognizable neurodevelopmental disorder Published: September 27, 2021 Publication: PLOS Genetics

Authors: Zineb Ammous, Lettie E Rawlins, Hannah Jones, Joseph S Leslie, Olivia Wenger, Ethan Scott, Jim Deline, Tom Herr, Rebecca Evans, Angela Scheid, Joanna Kennedy, Barry A Chioza, Ryan M Ames, Harold E Cross, Erik G Puffenberger, Lorna Harries, Emma L Baple, Andrew H Crosby

Abstract:
SNIP1 (Smad nuclear interacting protein 1) is a widely expressed transcriptional suppressor of the TGF-β signal-transduction pathway which plays a key role in human spliceosome function. Here, we describe extensive genetic studies and clinical findings of a complex inherited neurodevelopmental disorder in 35 individuals associated with a SNIP1 NM_024700.4:c.1097A>G, p.(Glu366Gly) variant, present at high frequency in the Amish community. The cardinal clinical features of the condition include hypotonia, global developmental delay, intellectual disability, seizures, and a characteristic craniofacial appearance. Our gene transcript studies in affected individuals define altered gene expression profiles of a number of molecules with well-defined neurodevelopmental and neuropathological roles, potentially explaining clinical outcomes. Together these data confirm this SNIP1 gene variant as a cause of an autosomal recessive complex neurodevelopmental disorder and provide important insight into the molecular roles of SNIP1, which likely explain the cardinal clinical outcomes in affected individuals, defining potential therapeutic avenues for future research.
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Title: Cortical overgrowth in a preclinical forebrain organoid model of CNTNAP2-associated autism spectrum disorder Published: September 1, 2021 Publication: Nature Communications

Authors: Job O de Jong, Ceyda Llapashtica, Matthieu Genestine, Kevin Strauss, Frank Provenzano, Yan Sun, Huixiang Zhu, Giuseppe P Cortese, Francesco Brundu, Karlla W Brigatti, Barbara Corneo, Bianca Migliori, Raju Tomer, Steven A Kushner, Christoph Kellendonk, Jonathan A Javitch, Bin Xu, Sander Markx

Abstract:
We utilized forebrain organoids generated from induced pluripotent stem cells of patients with a syndromic form of Autism Spectrum Disorder (ASD) with a homozygous protein-truncating mutation in CNTNAP2, to study its effects on embryonic cortical development. Patients with this mutation present with clinical characteristics of brain overgrowth. Patient-derived forebrain organoids displayed an increase in volume and total cell number that is driven by increased neural progenitor proliferation. Single-cell RNA sequencing revealed PFC-excitatory neurons to be the key cell types expressing CNTNAP2. Gene ontology analysis of differentially expressed genes (DEgenes) corroborates aberrant cellular proliferation. Moreover, the DEgenes are enriched for ASD-associated genes. The cell-type-specific signature genes of the CNTNAP2-expressing neurons are associated with clinical phenotypes previously described in patients. The organoid overgrowth phenotypes were largely rescued after correction of the mutation using CRISPR-Cas9. This CNTNAP2-organoid model provides opportunity for further mechanistic inquiry and development of new therapeutic strategies for ASD.
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Title: Defects in lymphocyte telomere homeostasis contribute to cellular immune phenotype in patients with cartilage-hair hypoplasia Published: October 1, 2017 Publication: Journal of Allergy and Clinical Immunology

Authors: Aubert G, Strauss KA, Lansdorp PM, Rider NL

Abstract:
Mutations in the long noncoding RNA RNase component of the mitochondrial RNA processing endoribonuclease (RMRP) give rise to the autosomal recessive condition cartilage-hair hypoplasia (CHH). The CHH disease phenotype has some overlap with dyskeratosis congenita, a well-known "telomere disorder." RMRP binds the telomerase reverse transcriptase (catalytic subunit) in some cell lines, raising the possibility that RMRP might play a role in telomere biology.
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Title: Gangliosides and Hearing Published: May 30, 2017 Publication: BBA - General Subjects

Authors: Inokuchi JI, Go S, Yoshikawa M, Strauss K

Abstract:
Severe auditory impairment observed in GM3 synthase-deficient mice and humans indicates that glycosphingolipids, especially sialic-acid containing gangliosides, are indispensable for hearing. Gangliosides associate with glycoproteins to form membrane microdomains, the composition of which plays a special role in maintaining the structural and functional integrity of hair cells. These microdomains, also called lipid rafts, connect with intracellular signaling and cytoskeletal systems to link cellular responses to environmental cues. During development, ganglioside species are expressed in distinctive spatial and temporal patterns throughout the cochlea. In both mice and humans, blocking particular steps of ganglioside metabolism produces distinctive neurological and auditory phenotypes. Thus each ganglioside species may have specific, non-overlapping functions within the cochlea, central auditory network, and brain.
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Title: Abnormal Hypermethylation at Imprinting Control Regions in Patients with S-Adenosylhomocysteine Hydrolase (AHCY) Deficiency. Published: March 14, 2016 Publication: PLOS One

Authors: Motzek A, Knezevic J, Switzeny OJ, Cooper A, Baric I, Beluzic R, Strauss KA, Puffenberger EG, Mudd SH, Vugrek O, Zechner U

Abstract:
S-adenosylhomocysteine hydrolase (AHCY) deficiency is a rare autosomal recessive disorder in methionine metabolism caused by mutations in the AHCY gene. Main characteristics are psychomotor delay including delayed myelination and myopathy (hypotonia, absent tendon reflexes etc.) from birth, mostly associated with hypermethioninaemia, elevated serum creatine kinase levels and increased genome wide DNA methylation. The prime function of AHCY is to hydrolyse and efficiently remove S-adenosylhomocysteine, the by-product of transmethylation reactions and one of the most potent methyltransferase inhibitors. In this study, we set out to more specifically characterize DNA methylation changes in blood samples from patients with AHCY deficiency. Global DNA methylation was increased in two of three analysed patients. In addition, we analysed the DNA methylation levels at differentially methylated regions (DMRs) of six imprinted genes (MEST, SNRPN, LIT1, H19, GTL2 and PEG3) as well as Alu and LINE1 repetitive elements in seven patients. Three patients showed a hypermethylation in up to five imprinted gene DMRs. Abnormal methylation in Alu and LINE1 repetitive elements was not observed. We conclude that DNA hypermethylation seems to be a frequent but not a constant feature associated with AHCY deficiency that affects different genomic regions to different degrees. Thus AHCY deficiency may represent an ideal model disease for studying the molecular origins and biological consequences of DNA hypermethylation due to impaired cellular methylation status.
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Title: Ganglioside GM3 is essential for the structural integrity and function of cochlear hair cells Published: March 5, 2015 Publication: Human Molecular Genetics

Authors: Yoshikawa M, Go S, Suzuki S, Suzuki A, Katori Y, Morlet T, Gottlieb SM, Fujiwara M, Iwasaki K, Strauss KA, Inokuchi J

Abstract:
GM3 synthase (ST3GAL5) is the first biosynthetic enzyme of a- and b-series gangliosides. Patients with GM3 synthase deficiency suffer severe neurological disability and deafness. Eight children (ages 4.1 ± 2.3 years) homozygous for ST3GAL5 c.694C>T had no detectable GM3 (a-series) or GD3 (b-series) in plasma. Their auditory function was characterized by the absence of middle ear muscle reflexes, distortion product otoacoustic emissions and cochlear microphonics, as well as abnormal auditory brainstem responses and cortical auditory-evoked potentials. In St3gal5−/−mice, stereocilia of outer hair cells showed signs of degeneration as early as postnatal Day 3 (P3); thereafter, blebs devoid of actin or tubulin appeared at the region of vestigial kinocilia, suggesting impaired vesicular trafficking. Stereocilia of St3gal5−/− inner hair cells were fused by P17, and protein tyrosine phosphatase receptor Q, normally linked to myosin VI at the tapered base of stereocilia, was maldistributed along the cell membrane. B4galnt1−/− (GM2 synthase-deficient) mice expressing only GM3 and GD3 gangliosides had normal auditory structure and function. Thus, GM3-dependent membrane microdomains might be essential for the proper organization and maintenance of stereocilia in auditory hair cells.
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Title: Severity of cardiomyopathy associated with adenine nucleotide translocator-1 deficiency correlates with mtDNA haplogroup Published: February 26, 2013 Publication: Proceedings of the National Academy of Sciences of the United States of America

Authors: Strauss KA, DuBiner L, Simon M, Zargoza M, Sengupta PP, Li P, Narula N, Dreike S, Platt J, Procaccio V, Ortiz-González XR, Puffenberger EG, Kelley RI, Morton DH, Narula J, Wallace DC

Abstract:
Mutations of both nuclear and mitochondrial DNA (mtDNA)–encoded mitochondrial proteins can cause cardiomyopathy associated with mitochondrial dysfunction. Hence, the cardiac phenotype of nuclear DNA mitochondrial mutations might be modulated by mtDNA variation. We studied a 13-generation Mennonite pedigree with autosomal recessive myopathy and cardiomyopathy due to an SLC25A4 frameshift null mutation (c.523delC, p.Q175RfsX38), which codes for the heart-muscle isoform of the adenine nucleotide translocator–1. Ten homozygous null (adenine nucleotide translocator–1−/−) patients monitored over a median of 6 years had a phenotype of progressive myocardial thickening, hyperalaninemia, lactic acidosis, exercise intolerance, and persistent adrenergic activation. Electrocardiography and echocardiography with velocity vector imaging revealed abnormal contractile mechanics, myocardial repolarization abnormalities, and impaired left ventricular relaxation. End-stage heart disease was characterized by massive, symmetric, concentric cardiac hypertrophy; widespread cardiomyocyte degeneration; overabundant and structurally abnormal mitochondria; extensive subendocardial interstitial fibrosis; and marked hypertrophy of arteriolar smooth muscle. Substantial variability in the progression and severity of heart disease segregated with maternal lineage, and sequencing of mtDNA from five maternal lineages revealed two major European haplogroups, U and H. Patients with the haplogroup U mtDNAs had more rapid and severe cardiomyopathy than those with haplogroup H.
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Title: Reduced thymic output, cell cycle abnormalities, and increased apoptosis of T lymphocytes in patients with cartilage-hair hypoplasia Published: July 1, 2011 Publication: Journal of Allergy and Clinical Immunology

Authors: de la Fuente MA, Recher M, Rider NL, Strauss KA, Morton DH, Adair M, Bonilla FA, Ochs HD, Gelfand EW, Pessach IM, Walter JE, King A, Giliani S, Pai SY, Notarangelo LD

Abstract:
Cartilage-hair hypoplasia (CHH) is characterized by metaphyseal dysplasia, bone marrow failure, increased risk of malignancies, and a variable degree of immunodeficiency. CHH is caused by mutations in the RNA component of the mitochondrial RNA processing (RMRP) endoribonuclease gene, which is involved in ribosomal assembly, telomere function, and cell cycle control.
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Title: Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia Published: February 1, 2011 Publication: Annals of Neurology

Authors: Lancaster E, Huijbers MG, Bar V, Boronat A, Wong A, Martinez-Hernandez E, Wilson C, Jacobs D, Lai M, Walker RW, Graus F, Bataller L, Illa I, Markx S, Strauss KA, Peles E, Scherer SS, Dalmau J

Abstract:
To report clinical and immunological investigations of contactin-associated proteinlike 2 (Caspr2), an autoantigen of encephalitis and peripheral nerve hyperexcitability (PNH) previously attributed to voltage-gated potassium channels (VGKC).
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Title: Cerebral haemodynamics in patients with glutaryl-coenzyme A dehydrogenase deficiency Published: January 1, 2010 Publication: Brain

Authors: Strauss KA, Donnelly P, Wintermark M

Abstract:
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.
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Title: Mutations in cystathionine beta-synthase or methylenetetrahydrofolate reductase gene increase N-homocysteinylated protein levels in humans Published: December 1, 2008 Publication: The FASEB Journal

Authors: Jakubowski H, Boers GH, Strauss KA

Abstract:
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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Title: Multimodal imaging of striatal degeneration in Amish patients with glutaryl-CoA dehydrogenase deficiency Published: July 1, 2007 Publication: Brain

Authors: Strauss KA, Lazovic J, Wintermark M, Morton DH

Abstract:
Despite early diagnosis, one-third of Amish infants with glutaryl-CoA dehydrogenase deficiency (GA1) develop striatal lesions that leave them permanently disabled. To better understand mechanisms of striatal degeneration, we retrospectively studied imaging results from 25 Amish GA1 patients homozygous for 1296C>T mutations in GCDH. Asymptomatic infants had reduced glucose tracer uptake and increased blood volume throughout gray matter, which may signify a predisposition to brain injury. Nine children (36%) developed striatal lesions: three had sudden motor regression during infancy whereas six had insidious motor delay associated with striatal lesions of undetermined onset. Acute striatal necrosis consisted of three stages: (1) an acute stage, within 24 h of motor regression, characterized by cytotoxic oedema within the basal ganglia, cerebral oligemia, and rapid transit of blood throughout gray matter; (2) a sub-acute stage, 4–5 days after the onset of clinical signs, characterized by reduced striatal perfusion and glucose uptake, and supervening vasogenic oedema; and (3) a chronic stage of striatal atrophy. Apparent diffusion coefficient maps revealed that at least two of the six patients with insidious motor delay suffered striatal injuries before or shortly after birth, followed by latent periods of several months before disability was apparent. Thus, acute and insidious presentations may occur by similar mechanisms, and differ only with regard to the timing of injury. Intravenous fluid and dextrose therapy for illnesses during the first 2 years of life was the only intervention that was clearly neuroprotective in this cohort (odds ratio for brain injury = 0.04, 95% confidence interval = 0.01–0.34; P < 0.001).
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Title: Mutations in methylenetetrahydrofolate reductase or cystathionine beta-synthase gene, or a high-methionine diet, increase homocysteine thiolactone levels in humans and mice Published: June 1, 2007 Publication: The FASEB Journal

Authors: Chwatko G, Boers GH, Strauss KA, Shih DM, Jakubowski H

Abstract:
Genetic disorders of homocysteine(Hcy) metabolism or a high-methionine diet lead toelevations of plasma Hcy levels. In humans, severegenetic hyperhomocysteinemia results in prematuredeath from vascular complications whereas dietaryhyperhomocysteinemia is often used to induce athero-sclerosis in animal models. Hcy is mistakenly selectedin place of methionine by methionyl-tRNA synthetaseduring protein biosynthesis, which results in the forma-tion of Hcy-thiolactone and initiates a pathophysiolog-ical pathway that has been implicated in human vasculardisease. However, whether genetic deficiencies in Hcymetabolism or a high-methionine diet affect Hcy-thio-lactone levels in mammals has been unknown. Here weshow that plasma Hcy-thiolactone is elevated 59-foldand 72-fold in human patients with hyperhomocysteine-mia secondary to mutations in methylenetetrahydrofo-late reductase and cystathionine -synthase genes, re-spectively. We also show that mice, like humans,eliminate Hcy-thiolactone by urinary excretion; in con-trast to humans, however, mice also eliminate signifi-cant amounts of plasma total Hcy (38%) by urinaryexcretion. In mice, hyperhomocysteinemia secondaryto a high-methionine diet leads to 3.7-fold and 25-foldincreases in plasma and urinary Hcy-thiolactone levels,respectively. Thus, we conclude that hyperhomocys-teinemia leads to significant increases in the athero-genic metabolite Hcy-thiolactone in humans and mice.
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Title: Cellular fate of truncated slow skeletal muscle troponin T produced by Glu180 nonsense mutation in amish nemaline myopathy Published: April 8, 2005 Publication: Journal of Biological Chemistry

Authors: Wang X, Huang QQ, Breckenridge MT, Chen A, Crawford TO, Morton DH, Jin JP

Abstract:
A nonsense mutation at codon Glu180 in exon 11 of slow skeletal muscle troponin T (TnT) gene (TNNT1) causes an autosomal-recessive inherited nemaline myopathy. We previously reported the absence of intact or prematurely terminated slow TnT polypeptide in Amish nemaline myopathy (ANM) patient muscle. The present study further investigates the expression and fate of mutant slow TnT in muscle cells. Intact slow TnT mRNA was readily detected in patient muscle, indicating unaffected transcription and RNA splicing. Sequence of the cloned cDNAs revealed the single nucleotide mutation in two alternatively spliced isoforms of slow TnT mRNA. Mutant TNNT1 cDNA is translationally active in Escherichia coli and non-muscle eukaryotic cells, producing the expected truncated slow TnT protein. The mutant mRNA was expressed at significant levels in differentiated C2C12 myotubes, but unlike intact exogenous TnT, truncated slow TnT protein was not detected. Transfective expression in undifferentiated myoblasts produced slow TnT mRNA but not a detectable amount of truncated or intact slow TnT proteins, indicating a muscle cell-specific proteolysis of TnT when it is not integrated into myofilaments. The slow TnT-(1–179) fragment has substantially lower affinity for binding to tropomyosin, in keeping with the loss of one of two tropomyosin-binding sites. Our findings suggest that inefficient incorporation into myofilament is responsible for the instability of mutant slow TnT in ANM muscle. Rapid degradation of the truncated slow TnT protein, rather than instability of the nonsense mRNA, provides the protective mechanism against the potential dominant negative effect of the mutant TnT fragment.
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Title: Challenges for basic research in glutaryl-CoA dehydrogenase deficiency Published: January 1, 2004 Publication: Journal of Inherited Metabolic Disease

Authors: Kölker S, Strauss KA, Goodman SI, Hoffmann GF, Okun JG, Koeller DM

Abstract:
During the last decades, efforts have been made to elucidate the complex mechanisms underlying neuronal damage in glutaryl-CoA dehydrogenase deficiency. A combination of in vitro and in vivo investigations have facilitated the development of several hypotheses, including the probable pathogenic role of accumulating glutaric acid and 3-hydroxyglutaric acid. However, there are still many shortcomings that limit an evidence-based approach to treating this inborn error of metabolism. Major future goals should include generation of a suitable animal model for acute striatal necrosis, investigation of the formation, distribution and exact intra- and extracellular concentrations of accumulating metabolites, a deeper understanding of striatal vulnerability, and systematic investigation of effects on cerebral gene expression during development and of the modulatory role of inflammatory cytokines.
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Title: Vascular dysfunction as an additional pathomechanism in glutaric aciduria type I Published: January 1, 2004 Publication: Journal of Inherited Metabolic Disease

Authors: Mühlhausen C, Ergün S, Strauss KA, Koeller DM, Crnic L, Woontner M, Goodman SI, Ullrich K, Braulke T

Abstract:
The metabolic hallmark of glutaric aciduria type I (GA I) is the deficiency of glutaryl-CoA dehydrogenase (GCDH) with subsequent accumulation of glutaric acid, 3-hydroxglutaric acid (3-OH-GA) and glutaconic acid. Current concepts regarding pathomechanisms of GA I focus on investigations of excitotoxic effects of 3-OH-GA. To identify pathogenetically relevant genes, microarray analyses were performed using brain material from GCDH-deficient (GCDH (-/-)) and control mice. These microarray data confirmed recent pathogenic models, but also revealed alterations in genes that had previously not been correlated to the disease, e.g. genes concerning vascular biology. Subsequent in vitro and in vivo experiments confirmed direct effects of 3-OH-GA on vascular permeability and endothelial integrity. Clinical observations underscore the involvement of vascular dysfunction. In MRI scans of GA I patients, subdural effusions as well as dilated transarachnoid vascular plexuses were detected independently of encephalopathic crises. In fact, some of these findings are already detectable shortly after birth. MRI scans of a GA I patient performed during an acute encephalopathic crisis detected a dilated intrastriatal vasculature with perivascular hyperintensity, indicating local extravasation. In conclusion, we hypothesize that 3-OH-GA affects prenatal development of vessels, thus leading to an increased vulnerability of endothelial structures and subsequent vascular dysfunction. These observations display an additional pathomechanism in GA I and might explain frontotemporal hypoplasia and chronic subdural effusions in this disease. Elucidation of the pathomechanisms of vascular dysfunction may give further insights into the pathogenesis of GA I.
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Title: Truncation by Glu180 nonsense mutation results in complete loss of slow skeletal muscle troponin T in a lethal nemaline myopathy Published: July 1, 2003 Publication: Journal of Biological Chemistry

Authors: Jin JP, Brotto MA, Hossain MM, Huang QQ, Brotto LS, Nosek TM, Morton DH, Crawford TO

Abstract:
A lethal form of nemaline myopathy, named “Amish Nemaline Myopathy” (ANM), is linked to a nonsense mutation at codon Glu180 in the slow skeletal muscle troponin T (TnT) gene. We found that neither the intact nor the truncated slow TnT protein was present in the muscle of patients with ANM. The complete loss of slow TnT is consistent with the observed recessive pattern of inheritance of the disease and indicates a critical role of the COOH-terminal T2 domain in the integration of TnT into myofibrils. Expression of slow and fast isoforms of TnT is fiber-type specific. The lack of slow TnT results in selective atrophy of type 1 fibers. Slow TnT confers a higher Ca2+ sensitivity than does fast TnT in single fiber contractility assays. Despite the lack of slow TnT, individuals with ANM have normal muscle power at birth. The postnatal onset and infantile progression of ANM correspond to a down-regulation of cardiac and embryonic splice variants of fast TnT in normal developing human skeletal muscle, suggesting that the fetal TnT isoforms complement slow TnT. These results lay the foundation for understanding the molecular pathophysiology and the potential targeted therapy of ANM.
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