{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T05:04:20Z","timestamp":1780376660328,"version":"3.54.1"},"reference-count":21,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2021,7,16]],"date-time":"2021-07-16T00:00:00Z","timestamp":1626393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Recherche Hospitalo-Universitaire","award":["16-RHUS-0004"],"award-info":[{"award-number":["16-RHUS-0004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,10,22]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Heterozygous missense HTRA1 mutations have been associated with an autosomal dominant cerebral small vessel disease (CSVD) whereas the pathogenicity of heterozygous HTRA1 stop codon variants is unclear. We performed a targeted high throughput sequencing of all known CSVD genes, including HTRA1, in 3853 unrelated consecutive CSVD patients referred for molecular diagnosis. The frequency of heterozygous HTRA1 mutations leading to a premature stop codon in this patient cohort was compared with their frequency in large control databases. An analysis of HTRA1 mRNA was performed in several stop codon carrier patients. Clinical and neuroimaging features were characterized in all probands. Twenty unrelated patients carrying a heterozygous HTRA1 variant leading to a premature stop codon were identified. A highly significant difference was observed when comparing our patient cohort with control databases: gnomAD v3.1.1 [P\u2009=\u20093.12 \u00d7 10\u221217, odds ratio (OR) = 21.9], TOPMed freeze 5 (P\u2009=\u20097.6 \u00d7 10\u221218, OR = 27.1) and 1000 Genomes (P\u2009=\u20091.5 \u00d7 10\u22125). Messenger RNA analysis performed in eight patients showed a degradation of the mutated allele strongly suggesting a haploinsufficiency. Clinical and neuroimaging features are similar to those previously reported in heterozygous missense mutation carriers, except for penetrance, which seems lower. Altogether, our findings strongly suggest that heterozygous HTRA1 stop codons are pathogenic through a haploinsufficiency mechanism. Future work will help to estimate their penetrance, an important information for genetic counselling.<\/jats:p>","DOI":"10.1093\/brain\/awab271","type":"journal-article","created":{"date-parts":[[2021,7,15]],"date-time":"2021-07-15T19:11:04Z","timestamp":1626376264000},"page":"2616-2624","source":"Crossref","is-referenced-by-count":22,"title":["Heterozygous<i>HTRA1<\/i>nonsense or frameshift mutations are pathogenic"],"prefix":"10.1093","volume":"144","author":[{"given":"Thibault","family":"Coste","sequence":"first","affiliation":[{"name":"AP-HP, Service de G\u00e9n\u00e9tique Mol\u00e9culaire Neurovasculaire, H\u00f4pital Saint-Louis, France"},{"name":"Universit\u00e9 de Paris, INSERM UMR-1141 Neurodiderot, Paris F-75019, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Herv\u00e9","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, INSERM UMR-1141 Neurodiderot, Paris F-75019, France"},{"name":"AP-HP, CERVCO, Service de Neurologie, H\u00f4pital Lariboisi\u00e8re, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean Philippe","family":"Neau","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Universitaire de Poitiers, Service de Neurologie, Poitiers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7797-2236","authenticated-orcid":false,"given":"Eric","family":"Jouvent","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, INSERM UMR-1141 Neurodiderot, Paris F-75019, France"},{"name":"AP-HP, CERVCO, Service de Neurologie, H\u00f4pital Lariboisi\u00e8re, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatoumata","family":"Ba","sequence":"additional","affiliation":[{"name":"AP-HP, Service de G\u00e9n\u00e9tique Mol\u00e9culaire Neurovasculaire, H\u00f4pital Saint-Louis, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7oise","family":"Bergametti","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, INSERM UMR-1141 Neurodiderot, Paris F-75019, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Lamy","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Universitaire de Poitiers, Service de Neurologie, Poitiers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Cogez","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Universitaire de Caen, Service de Neurologie, Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Derache","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Universitaire de Caen, Service de Neurologie, Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romain","family":"Schneckenburger","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Universitaire de Caen, Service de Neurologie, Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maude","family":"Grelet","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Intercommunal de Toulon- La Seyne sur mer, Service de G\u00e9n\u00e9tique M\u00e9dicale, Toulon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9dric","family":"Gollion","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Universitaire de Toulouse, Service de Neurologie, Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Livia","family":"Lanotte","sequence":"additional","affiliation":[{"name":"H\u00f4pital De Hautepierre, Service de Neurologie, Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9rie","family":"Lauer","sequence":"additional","affiliation":[{"name":"H\u00f4pital De Hautepierre, Unit\u00e9 Neuro-Vasculaire, Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9rie","family":"Layet","sequence":"additional","affiliation":[{"name":"Groupe Hospitalier Du havre, Service de G\u00e9n\u00e9tique M\u00e9dicale, Le Havre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9dric","family":"Urbanczyk","sequence":"additional","affiliation":[{"name":"Centre Hospitalier D\u00e9partemental La Roche-Sur-Yon, Service de Neurologie, La Roche-Sur-Yon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mira","family":"Didic","sequence":"additional","affiliation":[{"name":"APHM, H\u00f4pital Timone Adultes, Service de Neurologie et Neuropsychologie, Marseille, France"},{"name":"Aix Marseille Universit\u00e9, INSERM, INS, Inst Neurosci Syst, Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Raynouard","sequence":"additional","affiliation":[{"name":"Fondation Adolphe de Rothschild, Service de Neurologie, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laure","family":"Delaval","sequence":"additional","affiliation":[{"name":"AP-HP, H\u00f4pital Bichat, Service de M\u00e9decine Interne, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9r\u00e9mie","family":"Dassa","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Emile Roux, Service de Neurologie, Le Puy-en-Velay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandru","family":"Florea","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Marie Madeleine, Service de Neurologie, Forbach, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Badiu","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Metz-Thionville, Service de Neurologie, Metz, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karine","family":"Nguyen","sequence":"additional","affiliation":[{"name":"APHM, H\u00f4pital Timone Adultes, D\u00e9partement de G\u00e9n\u00e9tique, Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Tournier-Lasserve","sequence":"additional","affiliation":[{"name":"AP-HP, Service de G\u00e9n\u00e9tique Mol\u00e9culaire Neurovasculaire, H\u00f4pital Saint-Louis, France"},{"name":"Universit\u00e9 de Paris, INSERM UMR-1141 Neurodiderot, Paris F-75019, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,7,16]]},"reference":[{"issue":"6","key":"2021103110140335800_awab271-B1","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1111\/ene.14183","article-title":"Monogenic cerebral small-vessel diseases: Diagnosis and therapy. Consensus recommendations of the European Academy of Neurology","volume":"27","author":"Mancuso","year":"2020","journal-title":"Eur J Neurol"},{"issue":"17","key":"2021103110140335800_awab271-B2","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1056\/NEJMoa0801560","article-title":"Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease","volume":"360","author":"Hara","year":"2009","journal-title":"N Engl J Med"},{"issue":"Pt 8","key":"2021103110140335800_awab271-B3","doi-asserted-by":"crossref","first-page":"2347","DOI":"10.1093\/brain\/awv155","article-title":"Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease","volume":"138","author":"Verdura","year":"2015","journal-title":"Brain"},{"issue":"11","key":"2021103110140335800_awab271-B4","doi-asserted-by":"crossref","first-page":"3447","DOI":"10.1161\/STROKEAHA.114.004236","article-title":"Features of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy","volume":"45","author":"Nozaki","year":"2014","journal-title":"Stroke"},{"issue":"10","key":"2021103110140335800_awab271-B5","doi-asserted-by":"crossref","first-page":"3007","DOI":"10.1161\/STROKEAHA.120.029517","article-title":"Beyond the brain: Systematic review of extracerebral phenotypes associated with monogenic cerebral small vessel disease","volume":"51","author":"Rannikm\u00e4e","year":"2020","journal-title":"Stroke"},{"issue":"21","key":"2021103110140335800_awab271-B6","doi-asserted-by":"crossref","first-page":"1964","DOI":"10.1212\/WNL.0000000000002694","article-title":"Distinct molecular mechanisms of HTRA1mutants in manifesting heterozygotes with CARASIL","volume":"86","author":"Nozaki","year":"2016","journal-title":"Neurology"},{"key":"2021103110140335800_awab271-B7","doi-asserted-by":"crossref","first-page":"693","DOI":"10.3389\/fneur.2019.00693","article-title":"HTRA1 mutations identified in symptomatic carriers have the property of interfering the trimer-dependent activation cascade","volume":"10","author":"Uemura","year":"2019","journal-title":"Front Neurol"},{"key":"2021103110140335800_awab271-B8","doi-asserted-by":"crossref","first-page":"545","DOI":"10.3389\/fneur.2020.00545","article-title":"HTRA1-related cerebral small vessel disease: A review of the literature","volume":"11","author":"Uemura","year":"2020","journal-title":"Front Neurol"},{"key":"2021103110140335800_awab271-B9","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.jns.2016.01.037","article-title":"Unusual case of cerebral small vessel disease with a heterozygous nonsense mutation in HTRA1","volume":"362","author":"Tateoka","year":"2016","journal-title":"J Neurol Sci"},{"issue":"7","key":"2021103110140335800_awab271-B10","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1161\/STROKEAHA.118.021283","article-title":"Characterization of heterozygous HTRA1 mutations in taiwanese patients with cerebral small vessel disease","volume":"49","author":"Lee","year":"2018","journal-title":"Stroke"},{"key":"2021103110140335800_awab271-B11","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.jns.2018.02.043","article-title":"Cerebral small vessel disease caused by a novel heterozygous mutation in HTRA1","volume":"388","author":"Thaler","year":"2018","journal-title":"J Neurol Sci"},{"issue":"3","key":"2021103110140335800_awab271-B12","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1007\/s10072-017-3231-z","article-title":"Two novel heterozygous HTRA1 mutations in two pedigrees with cerebral small vessel disease families","volume":"39","author":"Zhang","year":"2018","journal-title":"Neurol Sci"},{"issue":"10","key":"2021103110140335800_awab271-B13","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.2169\/internalmedicine.4041-19","article-title":"Cerebral small vessel disease related to a heterozygous nonsense mutation in HTRA1","volume":"59","author":"Ohta","year":"2020","journal-title":"Intern Med"},{"issue":"3","key":"2021103110140335800_awab271-B14","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1242\/jcs.181008","article-title":"Nonsense-mediated mRNA decay in humans at a glance","volume":"129","author":"Kurosaki","year":"2016","journal-title":"J Cell Sci"},{"issue":"6","key":"2021103110140335800_awab271-B15","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/S0968-0004(98)01208-0","article-title":"A rule for termination-codon position within intron-containing genes: When nonsense affects RNA abundance","volume":"23","author":"Nagy","year":"1998","journal-title":"Trends Biochem Sci"},{"issue":"8","key":"2021103110140335800_awab271-B16","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1007\/s10072-015-2121-5","article-title":"A frameshift mutation in HTRA1 expands CARASIL syndrome and peripheral small arterial disease to the Chinese population","volume":"36","author":"Cai","year":"2015","journal-title":"Neurol Sci"},{"issue":"4","key":"2021103110140335800_awab271-B17","doi-asserted-by":"crossref","first-page":"e345","DOI":"10.1212\/NXG.0000000000000345","article-title":"Novel mutation in HTRA1 in a family with diffuse white matter lesions and inflammatory features","volume":"5","author":"Ziaei","year":"2019","journal-title":"Neurol Genet"},{"issue":"11","key":"2021103110140335800_awab271-B18","doi-asserted-by":"crossref","first-page":"104354","DOI":"10.1016\/j.jstrokecerebrovasdis.2019.104354","article-title":"A case of leukoencephalopathy and small vessels disease caused by a novel HTRA1 homozygous mutation","volume":"28","author":"G\u00fcnd\u00fcz","year":"2019","journal-title":"J Stroke Cerebrovasc Dis"},{"key":"2021103110140335800_awab271-B19","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.wneu.2020.05.128","article-title":"Genetically confirmed CARASIL: Case report with novel HTRA1 mutation and literature review","volume":"143","author":"Yu","year":"2020","journal-title":"World Neurosurg"},{"issue":"10","key":"2021103110140335800_awab271-B20","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1212\/WNL.0000000000000202","article-title":"Two novel HTRA1 mutations in a European CARASIL patient","volume":"82","author":"Bianchi","year":"2014","journal-title":"Neurology"},{"issue":"23","key":"2021103110140335800_awab271-B21","doi-asserted-by":"crossref","first-page":"2392","DOI":"10.1212\/WNL.0000000000004710","article-title":"CARASIL families from India with 3 novel null mutations in the HTRA1 gene","volume":"89","author":"Preethish-Kumar","year":"2017","journal-title":"Neurology"}],"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awab271\/40435137\/awab271.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/brain\/article-pdf\/144\/9\/2616\/40880386\/awab271.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/brain\/article-pdf\/144\/9\/2616\/40880386\/awab271.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T07:27:10Z","timestamp":1725434830000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/article\/144\/9\/2616\/6322988"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,16]]},"references-count":21,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,7,16]]},"published-print":{"date-parts":[[2021,10,22]]}},"URL":"https:\/\/doi.org\/10.1093\/brain\/awab271","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,9,1]]},"published":{"date-parts":[[2021,7,16]]}}}