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Current therapeutic efforts aim to suppress expression of total or mutant huntingtin, though the relationship of huntingtin\u2019s normal activities to the gain-of-function mechanism and what the effects of huntingtin-lowering might be are unclear. Here, we have re-investigated a rare family segregating two presumed HTT loss-of-function (LoF) variants associated with the developmental disorder, Lopes-Maciel-Rodan syndrome (LOMARS), using whole-genome sequencing of DNA from cell lines, in conjunction with analysis of mRNA and protein expression. Our findings correct the muddled annotation of these HTT variants, reaffirm they are the genetic cause of the LOMARS phenotype and demonstrate that each variant is a huntingtin hypomorphic mutation. The NM_002111.8: c.4469+1G&amp;gt;A splice donor variant results in aberrant (exon 34) splicing and severely reduced mRNA, whereas, surprisingly, the NM_002111.8: c.8157T&amp;gt;A NP_002102.4: Phe2719Leu missense variant results in abnormally rapid turnover of the Leu2719 huntingtin protein. Thus, although rare and subject to an as yet unknown LoF intolerance at the population level, bona fide HTT LoF variants can be transmitted by normal individuals leading to severe consequences in compound heterozygotes due to huntingtin deficiency.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa283","type":"journal-article","created":{"date-parts":[[2021,1,9]],"date-time":"2021-01-09T14:31:25Z","timestamp":1610202685000},"page":"135-148","source":"Crossref","is-referenced-by-count":40,"title":["Mutations causing Lopes-Maciel-Rodan syndrome are huntingtin hypomorphs"],"prefix":"10.1093","volume":"30","author":[{"given":"Roy","family":"Jung","sequence":"first","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Neurology, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yejin","family":"Lee","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Neurology, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"Barker","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Neurology, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Correia","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Neurology, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baehyun","family":"Shin","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Neurology, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Loupe","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Neurology, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan L","family":"Collins","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Medical and Population Genetics Program, The Broad Institute of M.I.T. and Harvard, Cambridge, MA, 02142, USA"},{"name":"Program in Bioinformatics and Integrative Genomics, Division of Medical Sciences, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Lucente","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Neurology, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayla","family":"Ruliera","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Neurology, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammy","family":"Gillis","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Neurology, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayalakshmi S","family":"Mysore","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Neurology, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lance","family":"Rodan","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA"},{"name":"Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Picker","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA"},{"name":"Department of Child and Adolescent Psychiatry, Boston Children's Hospital, Harvard Medical School, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong-Min","family":"Lee","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Neurology, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Howland","sequence":"additional","affiliation":[{"name":"CHDI Management\/CHDI Foundation Inc., Princeton, NJ 08540, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramee","family":"Lee","sequence":"additional","affiliation":[{"name":"CHDI Management\/CHDI Foundation Inc., Princeton, NJ 08540, 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and Harvard, Cambridge, MA, 02142, USA"},{"name":"Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4246-3356","authenticated-orcid":false,"given":"Ihn Sik","family":"Seong","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Neurology, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,1,11]]},"reference":[{"key":"2021070119530282100_ref1","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/0092-8674(93)90585-E","article-title":"A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes","volume":"72","author":"The Huntington's Disease Collaborative 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Genet."},{"key":"2021070119530282100_ref17","doi-asserted-by":"crossref","first-page":"3859","DOI":"10.1093\/hmg\/ddx286","article-title":"A modifier of Huntington's disease onset at the MLH1 locus","volume":"26","author":"Lee","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"2021070119530282100_ref18","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1016\/j.neuron.2016.02.003","article-title":"The biology of Huntingtin","volume":"89","author":"Saudou","year":"2016","journal-title":"Neuron"},{"key":"2021070119530282100_ref19","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1001\/jamaneurol.2020.0299","article-title":"Huntingtin-lowering therapies for Huntington disease: a review of the evidence of potential benefits and risks","volume":"77","author":"Leavitt","year":"2020","journal-title":"JAMA Neurol."},{"key":"2021070119530282100_ref20","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1056\/NEJMoa1900907","article-title":"Targeting Huntingtin expression in patients with Huntington's disease","volume":"380","author":"Tabrizi","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"2021070119530282100_ref21","doi-asserted-by":"crossref","first-page":"e11184","DOI":"10.7554\/eLife.11184","article-title":"Huntingtin's spherical solenoid structure enables polyglutamine tract-dependent modulation of its structure and function","volume":"5","author":"Vijayvargia","year":"2016","journal-title":"Elife"},{"key":"2021070119530282100_ref22","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/nature25502","article-title":"The cryo-electron microscopy structure of huntingtin","volume":"555","author":"Guo","year":"2018","journal-title":"Nature"},{"key":"2021070119530282100_ref23","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1016\/j.str.2020.06.008","article-title":"The Polyglutamine expansion at the N-terminal of Huntingtin protein modulates the dynamic configuration and phosphorylation of the C-terminal HEAT domain","volume":"28","author":"Jung","year":"2020","journal-title":"Structure"},{"key":"2021070119530282100_ref24","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/S0968-0004(03)00168-3","article-title":"The hunt for huntingtin function: interaction partners tell many different stories","volume":"28","author":"Harjes","year":"2003","journal-title":"Trends Biochem. 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Med. Genet."},{"key":"2021070119530282100_ref32","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/BF02257483","article-title":"Structure and expression of the Huntington's disease gene: evidence against simple inactivation due to an expanded CAG repeat","volume":"20","author":"Ambrose","year":"1994","journal-title":"Somat. Cell Mol. Genet."},{"key":"2021070119530282100_ref33","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1038\/ejhg.2016.74","article-title":"A novel neurodevelopmental disorder associated with compound heterozygous variants in the huntingtin gene","volume":"24","author":"Rodan","year":"2016","journal-title":"Eur. J. Hum. Genet."},{"key":"2021070119530282100_ref34","first-page":"1833","article-title":"A novel neurodevelopmental disorder associated with compound heterozygous variants in the huntingtin gene","volume":"24","author":"Rodan","year":"2016","journal-title":"Eur. J. Hum. Genet."},{"key":"2021070119530282100_ref35","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1093\/hmg\/ddx033","article-title":"Novel allele-specific quantification methods reveal no effects of adult onset CAG repeats on HTT mRNA and protein levels","volume":"26","author":"Shin","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"2021070119530282100_ref36","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1006\/nbdi.1996.0018","article-title":"Differential expression of normal and mutant Huntington's disease gene alleles","volume":"3","author":"Persichetti","year":"1996","journal-title":"Neurobiol. Dis."},{"key":"2021070119530282100_ref37","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1038\/aps.2016.31","article-title":"A high-throughput-compatible assay to measure the degradation of endogenous Huntingtin proteins","volume":"37","author":"Wu","year":"2016","journal-title":"Acta Pharmacol. Sin."},{"key":"2021070119530282100_ref38","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"2021070119530282100_ref39","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/nature22034","article-title":"Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity","volume":"544","author":"Saleheen","year":"2017","journal-title":"Nature"},{"key":"2021070119530282100_ref40","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/s41586-020-2267-z","article-title":"Evaluating drug targets through human loss-of-function genetic variation","volume":"581","author":"Minikel","year":"2020","journal-title":"Nature"},{"key":"2021070119530282100_ref41","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1093\/hmg\/ddp524","article-title":"Huntingtin facilitates polycomb repressive complex 2","volume":"19","author":"Seong","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"2021070119530282100_ref42","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1111\/bpa.12427","article-title":"RNA toxicity induced by expanded CAG repeats in Huntington's disease","volume":"26","author":"Marti","year":"2016","journal-title":"Brain Pathol."},{"key":"2021070119530282100_ref43","doi-asserted-by":"crossref","first-page":"6182","DOI":"10.1523\/JNEUROSCI.0857-08.2008","article-title":"Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice","volume":"28","author":"Gray","year":"2008","journal-title":"J. Neurosci."},{"key":"2021070119530282100_ref44","doi-asserted-by":"crossref","first-page":"10519","DOI":"10.1002\/jcb.28338","article-title":"Structural insights into the aggregation mechanism of huntingtin exon 1 protein fragment with different polyQ-lengths","volume":"120","author":"Priya","year":"2019","journal-title":"J. Cell. Biochem."},{"key":"2021070119530282100_ref45","doi-asserted-by":"crossref","first-page":"2366","DOI":"10.1073\/pnas.1221891110","article-title":"Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease","volume":"110","author":"Sathasivam","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2021070119530282100_ref46","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1126\/science.aax3338","article-title":"Huntington's disease alters human neurodevelopment","volume":"369","author":"Barnat","year":"2020","journal-title":"Science"},{"key":"2021070119530282100_ref47","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1016\/j.jmb.2019.01.034","article-title":"Deregulated splicing is a major mechanism of RNA-induced toxicity in Huntington's disease","volume":"431","author":"Schilling","year":"2019","journal-title":"J. Mol. Biol."},{"key":"2021070119530282100_ref48","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1136\/jmedgenet-2015-103568","article-title":"Identification of novel genetic causes of Rett syndrome-like phenotypes","volume":"53","author":"Lopes","year":"2016","journal-title":"J. Med. 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