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Lidov, Hart

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Lidov

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Lidov, Hart
Author's Publications: search.filters.isAuthorOfPublication.9a2d983f-34ea-4350-81ee-d2de19c28964

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    Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia
    (The Rockefeller University Press, 2015) Boisson, Bertrand; Laplantine, Emmanuel; Dobbs, Kerry; Cobat, Aurélie; Tarantino, Nadine; Hazen, Melissa; Lidov, Hart; Hopkins, Gregory; Du, Likun; Belkadi, Aziz; Chrabieh, Maya; Itan, Yuval; Picard, Capucine; Fournet, Jean-Christophe; Eibel, Hermann; Tsitsikov, Erdyni; Pai, Sung-Yun; Abel, Laurent; Al-Herz, Waleed; Casanova, Jean-Laurent; Israel, Alain; Notarangelo, Luigi
    Inherited, complete deficiency of human HOIL-1, a component of the linear ubiquitination chain assembly complex (LUBAC), underlies autoinflammation, infections, and amylopectinosis. We report the clinical description and molecular analysis of a novel inherited disorder of the human LUBAC complex. A patient with multiorgan autoinflammation, combined immunodeficiency, subclinical amylopectinosis, and systemic lymphangiectasia, is homozygous for a mutation in HOIP, the gene encoding the catalytic component of LUBAC. The missense allele (L72P, in the PUB domain) is at least severely hypomorphic, as it impairs HOIP expression and destabilizes the whole LUBAC complex. Linear ubiquitination and NF-κB activation are impaired in the patient’s fibroblasts stimulated by IL-1β or TNF. In contrast, the patient’s monocytes respond to IL-1β more vigorously than control monocytes. However, the activation and differentiation of the patient’s B cells are impaired in response to CD40 engagement. These cellular and clinical phenotypes largely overlap those of HOIL-1-deficient patients. Clinical differences between HOIL-1- and HOIP-mutated patients may result from differences between the mutations, the loci, or other factors. Our findings show that human HOIP is essential for the assembly and function of LUBAC and for various processes governing inflammation and immunity in both hematopoietic and nonhematopoietic cells.
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    The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States
    (2016) Reddy, Hemakumar M.; Cho, Kyung-Ah; Lek, Monkol; Estrella, Elicia; Valkanas, Elise; Jones, Michael D.; Mitsuhashi, Satomi; Darras, Basil; Amato, Anthony; Lidov, Hart; Brownstein, Catherine; Margulies, David; Yu, Timothy W.; Salih, Mustafa A.; Kunkel, Louis; MacArthur, Daniel; Kang, Peter B.
    The current study characterizes a cohort of limb-girdle muscular dystrophy (LGMD) in the United States using whole exome sequencing. Fifty-five families affected by LGMD were recruited using an institutionally-approved protocol. Exome sequencing was performed on probands and selected parental samples. Pathogenic mutations and co-segregation patterns were confirmed by Sanger sequencing. Twenty-two families (40%) had novel and previously reported pathogenic mutations, primarily in LGMD genes, but also in genes for Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, congenital myopathy, myofibrillar myopathy, inclusion body myopathy, and Pompe disease. One family was diagnosed via clinical testing. Dominant mutations were identified in COL6A1, COL6A3, FLNC, LMNA, RYR1, SMCHD1, and VCP, recessive mutations in ANO5, CAPN3, GAA, LAMA2, SGCA, and SGCG, and X-linked mutations in DMD. A previously reported variant in DMD was confirmed to be benign. Exome sequencing is a powerful diagnostic tool for LGMD. Despite careful phenotypic screening, pathogenic mutations were found in other muscle disease genes, largely accounting for the increased sensitivity of exome sequencing. Our experience suggests that broad sequencing panels are useful for these analyses due to the phenotypic overlap of many neuromuscular conditions. The confirmation of a benign DMD variant illustrates the potential of exome sequencing to help determine pathogenicity.
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    Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas
    (2014) Brastianos, Priscilla; Taylor-Weiner, Amaro; Manley, Peter E.; Jones, Robert T.; Dias-Santagata, Dora; Thorner, Aaron R.; Rodriguez, Fausto J.; Bernardo, Lindsay A.; Schubert, Laura; Sunkavalli, Ashwini; Shillingford, Nick; Calicchio, Monica L.; Lidov, Hart; Taha, Hala; Martinez-Lage, Maria; Santi, Mariarita; Storm, Phillip B.; Lee, John Y. K.; Palmer, James N.; Adappa, Nithin D.; Scott, R. Michael; Dunn, Ian; Laws, Edward; Stewart, Chip; Ligon, Keith; Hoang, Mai; Van Hummelen, Paul; Hahn, William; Louis, David; Resnick, Adam C.; Kieran, Mark W.; Getz, Gad; Santagata, Sandro
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    Mutations in the substrate binding glycine-rich loop of the mitochondrial processing peptidase-α protein (PMPCA) cause a severe mitochondrial disease
    (Cold Spring Harbor Laboratory Press, 2016) Joshi, Mugdha; Anselm, Irina; Shi, Jiahai; Bale, Tejus A.; Towne, Meghan; Schmitz-Abe, Klaus; Crowley, Laura; Giani, Felix C.; Kazerounian, Shideh; Markianos, Kyriacos; Lidov, Hart; Folkerth, Rebecca D.; Sankaran, Vijay; Agrawal, Pankaj
    We describe a large Lebanese family with two affected members, a young female proband and her male cousin, who had multisystem involvement including profound global developmental delay, severe hypotonia and weakness, respiratory insufficiency, blindness, and lactic acidemia—findings consistent with an underlying mitochondrial disorder. Whole-exome sequencing was performed on DNA from the proband and both parents. The proband and her cousin carried compound heterozygous mutations in the PMPCA gene that encodes for α-mitochondrial processing peptidase (α-MPP), a protein likely involved in the processing of mitochondrial proteins. The variants were located close to and postulated to affect the substrate binding glycine-rich loop of the α-MPP protein. Functional assays including immunofluorescence and western blot analysis on patient's fibroblasts revealed that these variants reduced α-MPP levels and impaired frataxin production and processing. We further determined that those defects could be rescued through the expression of exogenous wild-type PMPCA cDNA. Our findings link defective α-MPP protein to a severe mitochondrial disease.
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    AIFM1 mutation presenting with fatal encephalomyopathy and mitochondrial disease in an infant
    (Cold Spring Harbor Laboratory Press, 2017) Morton, Sarah; Prabhu, Sanjay; Lidov, Hart; Shi, Jiahai; Anselm, Irina; Brownstein, Catherine; Bainbridge, Matthew N.; Beggs, Alan; Vargas, Sara; Agrawal, Pankaj
    Apoptosis-inducing factor mitochondrion-associated 1 (AIFM1), encoded by the gene AIFM1, has roles in electron transport, apoptosis, ferredoxin metabolism, reactive oxygen species generation, and immune system regulation. Here we describe a patient with a novel AIFM1 variant presenting unusually early in life with mitochondrial disease, rapid deterioration, and death. Autopsy, at the age of 4 mo, revealed features of mitochondrial encephalopathy, myopathy, and involvement of peripheral nerves with axonal degeneration. In addition, there was microvesicular steatosis in the liver, thymic noninvolution, follicular bronchiolitis, and pulmonary arterial medial hypertrophy. This report adds to the clinical and pathological spectrum of disease related to AIFM1 mutations and provides insights into the role of AIFM1 in cellular function.
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    Mutations in the Satellite Cell Gene MEGF10 Cause a Recessive Congenital Myopathy with Minicores
    (Springer-Verlag, 2012) Mahoney, Lane J.; Myers, Jennifer A.; Estrella, Elicia A.; Duncan, Anna R.; Dey, Friederike; DeChene, Elizabeth T.; Blasko-Goehringer, Jessica M.; Bönnemann, Carsten G.; Mendell, Jerry R.; Nishino, Ichizo; Boyden, Steven Edward; Kawahara, Genri; Mitsuhashi, S; Darras, Basil; Lidov, Hart; Beggs, Alan; Kunkel, Louis; Kang, Peter Byung-Hoon
    We ascertained a nuclear family in which three of four siblings were affected with an unclassified autosomal recessive myopathy characterized by severe weakness, respiratory impairment, scoliosis, joint contractures, and an unusual combination of dystrophic and myopathic features on muscle biopsy. Whole genome sequence from one affected subject was filtered using linkage data and variant databases. A single gene, MEGF10, contained nonsynonymous mutations that co-segregated with the phenotype. Affected subjects were compound heterozygous for missense mutations c.976T > C (p.C326R) and c.2320T > C (p.C774R). Screening the MEGF10 open reading frame in 190 patients with genetically unexplained myopathies revealed a heterozygous mutation, c.211C > T (p.R71W), in one additional subject with a similar clinical and histological presentation as the discovery family. All three mutations were absent from at least 645 genotyped unaffected control subjects. MEGF10 contains 17 atypical epidermal growth factor-like domains, each of which contains eight cysteine residues that likely form disulfide bonds. Both the p.C326R and p.C774R mutations alter one of these residues, which are completely conserved in vertebrates. Previous work showed that murine Megf10 is required for preserving the undifferentiated, proliferative potential of satellite cells, myogenic precursors that regenerate skeletal muscle in response to injury or disease. Here, knockdown of megf10 in zebrafish by four different morpholinos resulted in abnormal phenotypes including unhatched eggs, curved tails, impaired motility, and disorganized muscle tissue, corroborating the pathogenicity of the human mutations. Our data establish the importance of MEGF10 in human skeletal muscle and suggest satellite cell dysfunction as a novel myopathic mechanism.