{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T05:36:15Z","timestamp":1784957775487,"version":"3.55.0"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2021,11,13]],"date-time":"2021-11-13T00:00:00Z","timestamp":1636761600000},"content-version":"vor","delay-in-days":43,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Intramural Research Program of the National Institute on Deafness and Other Communication Disorders","award":["Z1A-000046-18"],"award-info":[{"award-number":["Z1A-000046-18"]}]},{"name":"Extramural Research Program of the NIDCD","award":["R21DC015853"],"award-info":[{"award-number":["R21DC015853"]}]},{"name":"NIDCD or the National Institutes of Health"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Developmental stuttering is a common speech disorder with strong genetic underpinnings. Recently, stuttering has been associated with mutations in genes involved in lysosomal enzyme trafficking. However, how these mutations affect the brains of people who stutter remains largely unknown. In this study, we compared grey matter volume and white matter fractional anisotropy between a unique group of seven subjects who stutter and carry the same rare heterozygous AP4E1 coding mutations and seven unrelated controls without such variants. The carriers of the AP4E1 mutations are members of a large Cameroonian family in which the association between AP4E1 and persistent stuttering was previously identified. Compared to controls, mutation carriers showed reduced grey matter volume in the thalamus, visual areas and the posterior cingulate cortex. Moreover, reduced fractional anisotropy was observed in the corpus callosum, consistent with the results of previous neuroimaging studies of people who stutter with unknown genetic backgrounds. Analysis of gene expression data showed that these structural differences appeared at the locations in which expression of AP4E1 is relatively high. Moreover, the pattern of grey matter volume differences was significantly associated with AP4E1 expression across the left supratentorial regions. This spatial congruency further supports the connection between AP4E1 mutations and the observed structural differences.<\/jats:p>","DOI":"10.1093\/braincomms\/fcab266","type":"journal-article","created":{"date-parts":[[2021,11,9]],"date-time":"2021-11-09T20:18:16Z","timestamp":1636489096000},"source":"Crossref","is-referenced-by-count":6,"title":["Neuroanatomical anomalies associated with rare<i>AP4E1<\/i>mutations in people who stutter"],"prefix":"10.1093","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9333-4840","authenticated-orcid":false,"given":"Ho Ming","family":"Chow","sequence":"first","affiliation":[{"name":"Department of Communication Sciences and Disorders, University of Delaware, Newark, DE 19713, USA"},{"name":"Katzin Diagnostic & Research PET\/MR Center, Nemours\/Alfred duPont Hospital for Children, Wilmington, DE 19803, USA"},{"name":"Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Section on Genetics of Communication Disorders, NIDCD\/NIH, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Li","sequence":"additional","affiliation":[{"name":"Katzin Diagnostic & Research PET\/MR Center, Nemours\/Alfred duPont Hospital for Children, Wilmington, DE 19803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3661-6248","authenticated-orcid":false,"given":"Siyuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Section on Developmental Neurogenomics, NIMH\/NIH, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0598-4956","authenticated-orcid":false,"given":"Carlos","family":"Frigerio-Domingues","sequence":"additional","affiliation":[{"name":"Section on Genetics of Communication Disorders, NIDCD\/NIH, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Drayna","sequence":"additional","affiliation":[{"name":"Section on Genetics of Communication Disorders, NIDCD\/NIH, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,11,13]]},"reference":[{"issue":"2","key":"2021120108064581200_fcab266-B1","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1002\/mgg3.276","article-title":"Genetic contributions to stuttering: The current evidence","volume":"5","author":"Frigerio-Domingues","year":"2017","journal-title":"Mol Genet Genomic Med"},{"issue":"8","key":"2021120108064581200_fcab266-B2","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1056\/NEJMoa0902630","article-title":"Mutations in the lysosomal enzyme\u2013targeting pathway and persistent stuttering","volume":"362","author":"Kang","year":"2010","journal-title":"N Engl J Med"},{"issue":"5","key":"2021120108064581200_fcab266-B3","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/j.ajhg.2015.10.007","article-title":"Association between rare variants in AP4E1, a component of intracellular trafficking, and persistent stuttering","volume":"97","author":"Raza","year":"2015","journal-title":"Am J Hum Genet"},{"key":"2021120108064581200_fcab266-B4","first-page":"2495","volume-title":"The Metabolic and molecular bases of inherited disease","author":"Kornfeld","year":"1995"},{"issue":"5","key":"2021120108064581200_fcab266-B5","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1172\/JCI110189","article-title":"Fibroblasts from patients with I-cell disease and pseudo-Hurler polydystrophy are deficient in uridine 5\u2019-diphosphate-N-acetylglucosamine: Glycoprotein N-acetylglucosaminylphosphotransferase activity","volume":"67","author":"Reitman","year":"1981","journal-title":"J Clin Invest"},{"issue":"6","key":"2021120108064581200_fcab266-B6","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1016\/j.ajhg.2011.04.019","article-title":"Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature","volume":"88","author":"Abou Jamra","year":"2011","journal-title":"Am J Hum Genet"},{"issue":"2","key":"2021120108064581200_fcab266-B7","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1136\/jmg.2010.082263","article-title":"Adaptor protein complex-4 (AP-4) deficiency causes a novel autosomal recessive cerebral palsy syndrome with microcephaly and intellectual disability","volume":"48","author":"Moreno-De-Luca","year":"2011","journal-title":"J Med Genet"},{"issue":"4","key":"2021120108064581200_fcab266-B8","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/ejhg.2015.154","article-title":"Mucolipidosis types II and III and non-syndromic stuttering are associated with different variants in the same genes","volume":"24","author":"Raza","year":"2016","journal-title":"Eur J Hum Genet"},{"issue":"7","key":"2021120108064581200_fcab266-B9","doi-asserted-by":"crossref","first-page":"3345","DOI":"10.1002\/hbm.23590","article-title":"White matter developmental trajectories associated with persistence and recovery of childhood stuttering","volume":"38","author":"Chow","year":"2017","journal-title":"Hum Brain Mapp"},{"issue":"9","key":"2021120108064581200_fcab266-B10","first-page":"2670","article-title":"Anomalous morphology in left hemisphere motor and premotor cortex of children who stutter","volume":"141","author":"Garnett","year":"2018","journal-title":"Brain"},{"issue":"1","key":"2021120108064581200_fcab266-B11","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1093\/brain\/awx316","article-title":"Structural connectivity of right frontal hyperactive areas scales with stuttering severity","volume":"141","author":"Neef","year":"2018","journal-title":"Brain"},{"issue":"1","key":"2021120108064581200_fcab266-B12","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1007\/s00429-014-0912-8","article-title":"The frontal aslant tract underlies speech fluency in persistent developmental stuttering","volume":"221","author":"Kronfeld-Duenias","year":"2016","journal-title":"Brain Struct Funct"},{"issue":"8","key":"2021120108064581200_fcab266-B13","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1016\/j.cortex.2012.08.013","article-title":"A voxel-based morphometry (VBM) analysis of regional grey and white matter volume abnormalities within the speech production network of children who stutter","volume":"49","author":"Beal","year":"2013","journal-title":"Cortex"},{"key":"2021120108064581200_fcab266-B14","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.bandl.2013.05.013","article-title":"Disrupted white matter in language and motor tracts in developmental stuttering","volume":"131","author":"Connally","year":"2014","journal-title":"Brain Lang"},{"issue":"Pt 3","key":"2021120108064581200_fcab266-B15","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1093\/brain\/awu400","article-title":"White matter neuroanatomical differences in young children who stutter","volume":"138","author":"Chang","year":"2015","journal-title":"Brain"},{"key":"2021120108064581200_fcab266-B16","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.jfludis.2017.01.002","article-title":"Anomalous network architecture of the resting brain in children who stutter","volume":"55","author":"Chang","year":"2018","journal-title":"J Fluency Disord"},{"issue":"3","key":"2021120108064581200_fcab266-B17","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1162\/nol_a_00017","article-title":"Linking lysosomal enzyme targeting genes and energy metabolism with altered gray matter volume in children with persistent stuttering","volume":"1","author":"Chow","year":"2020","journal-title":"Neurobiol Lang"},{"key":"2021120108064581200_fcab266-B18","doi-asserted-by":"crossref","first-page":"101718","DOI":"10.1016\/j.pneurobio.2019.101718","article-title":"Neurofilament-lysosomal genetic intersections in the cortical network of stuttering","volume":"184","author":"Benito-Arag\u00f3n","year":"2020","journal-title":"Prog Neurobiol"},{"issue":"7416","key":"2021120108064581200_fcab266-B19","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/nature11405","article-title":"An anatomically comprehensive atlas of the adult human brain transcriptome","volume":"489","author":"Hawrylycz","year":"2012","journal-title":"Nature"},{"issue":"12","key":"2021120108064581200_fcab266-B20","doi-asserted-by":"crossref","first-page":"1832","DOI":"10.1038\/nn.4171","article-title":"Canonical genetic signatures of the adult human brain","volume":"18","author":"Hawrylycz","year":"2015","journal-title":"Nat Neurosci"},{"issue":"6240","key":"2021120108064581200_fcab266-B21","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1126\/science.1255905","article-title":"BRAIN NETWORKS. Correlated gene expression supports synchronous activity in brain networks","volume":"348","author":"Richiardi","year":"2015","journal-title":"Science"},{"issue":"26","key":"2021120108064581200_fcab266-B22","doi-asserted-by":"crossref","first-page":"6830","DOI":"10.1073\/pnas.1619121114","article-title":"Brain circuit-gene expression relationships and neuroplasticity of multisensory cortices in blind children","volume":"114","author":"Ortiz-Ter\u00e1n","year":"2017","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"9","key":"2021120108064581200_fcab266-B23","first-page":"2755","article-title":"Molecular properties underlying regional vulnerability to Alzheimer\u2019s disease pathology","volume":"141","author":"Grothe","year":"2018","journal-title":"Brain"},{"issue":"5","key":"2021120108064581200_fcab266-B24","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/j.biopsych.2017.10.019","article-title":"Brain regions showing white matter loss in Huntington\u2019s disease are enriched for synaptic and metabolic genes","volume":"83","author":"McColgan","year":"2018","journal-title":"Biol Psychiatry"},{"key":"2021120108064581200_fcab266-B25","volume-title":"SSI-3: Stuttering severity instrument for children and adults","author":"Riley","year":"1994","edition":"3rd"},{"key":"2021120108064581200_fcab266-B26","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1006\/nimg.2001.0786","article-title":"A voxel-based morphometric study of ageing in 465 normal adult human brains","volume":"14","author":"Good","year":"2001","journal-title":"Neuroimage"},{"issue":"1","key":"2021120108064581200_fcab266-B27","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.neuroimage.2007.07.007","article-title":"A fast diffeomorphic image registration algorithm","volume":"38","author":"Ashburner","year":"2007","journal-title":"Neuroimage"},{"issue":"Suppl 1","key":"2021120108064581200_fcab266-B28","doi-asserted-by":"crossref","first-page":"S208","DOI":"10.1016\/j.neuroimage.2004.07.051","article-title":"Advances in functional and structural MR image analysis and implementation as FSL","volume":"23","author":"Smith","year":"2004","journal-title":"Neuroimage"},{"issue":"4","key":"2021120108064581200_fcab266-B29","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1016\/j.neuroimage.2006.02.024","article-title":"Tract-based spatial statistics: Voxelwise analysis of multi-subject diffusion data","volume":"31","author":"Smith","year":"2006","journal-title":"Neuroimage"},{"key":"2021120108064581200_fcab266-B30","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.neuroimage.2014.01.060","article-title":"Permutation inference for the general linear model","volume":"92","author":"Winkler","year":"2014","journal-title":"Neuroimage"},{"issue":"9","key":"2021120108064581200_fcab266-B31","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/s11910-015-0579-4","article-title":"The neurobiological grounding of persistent stuttering: From structure to function","volume":"15","author":"Neef","year":"2015","journal-title":"Curr Neurol Neurosci Rep"},{"issue":"1","key":"2021120108064581200_fcab266-B32","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1006\/nimg.2001.0978","article-title":"Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain","volume":"15","author":"Tzourio-Mazoyer","year":"2002","journal-title":"Neuroimage"},{"issue":"7370","key":"2021120108064581200_fcab266-B33","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1038\/nature10523","article-title":"Spatio-temporal transcriptome of the human brain","volume":"478","author":"Kang","year":"2011","journal-title":"Nature"},{"issue":"1","key":"2021120108064581200_fcab266-B34","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.cortex.2009.02.017","article-title":"Altered effective connectivity and anomalous anatomy in the basal ganglia-thalamocortical circuit of stuttering speakers","volume":"46","author":"Lu","year":"2010","journal-title":"Cortex"},{"issue":"Pt 10","key":"2021120108064581200_fcab266-B35","doi-asserted-by":"crossref","first-page":"2747","DOI":"10.1093\/brain\/awp185","article-title":"How the brain repairs stuttering","volume":"132","author":"Kell","year":"2009","journal-title":"Brain"},{"issue":"3","key":"2021120108064581200_fcab266-B36","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1016\/j.neuroimage.2010.12.083","article-title":"Spatiotemporal signatures of an abnormal auditory system in stuttering","volume":"55","author":"Kikuchi","year":"2011","journal-title":"Neuroimage"},{"issue":"11","key":"2021120108064581200_fcab266-B37","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1093\/cercor\/bhr028","article-title":"Evidence of left inferior frontal\u2013premotor structural and functional connectivity deficits in adults who stutter","volume":"21","author":"Chang","year":"2011","journal-title":"Cereb Cortex"},{"key":"2021120108064581200_fcab266-B38","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.bandl.2016.08.009","article-title":"Grey matter volume differences in the left caudate nucleus of people who stutter","volume":"164","author":"Sowman","year":"2017","journal-title":"Brain Lang"},{"issue":"4","key":"2021120108064581200_fcab266-B39","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.jcomdis.2004.03.001","article-title":"Stuttering and the basal ganglia circuits: A critical review of possible relations","volume":"37","author":"Alm","year":"2004","journal-title":"J Commun Disord"},{"key":"2021120108064581200_fcab266-B40","doi-asserted-by":"crossref","first-page":"3088","DOI":"10.3389\/fpsyg.2019.03088","article-title":"Involvement of the cortico-basal ganglia-thalamocortical loop in developmental stuttering","volume":"10","author":"Chang","year":"2019","journal-title":"Front Psychol"},{"issue":"6","key":"2021120108064581200_fcab266-B41","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1177\/1073858418803594","article-title":"Functional and neuroanatomical bases of developmental stuttering: current insights","volume":"25","author":"Chang","year":"2019","journal-title":"Neuroscientist"},{"issue":"3","key":"2021120108064581200_fcab266-B42","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.bandl.2013.05.016","article-title":"Computational modeling of stuttering caused by impairments in a basal ganglia thalamo-cortical circuit involved in syllable selection and initiation","volume":"126","author":"Civier","year":"2013","journal-title":"Brain Lang"},{"issue":"5","key":"2021120108064581200_fcab266-B43","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.jneuroling.2009.08.006","article-title":"A neural theory of speech acquisition and production","volume":"25","author":"Guenther","year":"2012","journal-title":"J Neurolinguistics"},{"issue":"6","key":"2021120108064581200_fcab266-B44","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1016\/S0959-4388(00)00153-7","article-title":"Complementary roles of basal ganglia and cerebellum in learning and motor control","volume":"10","author":"Doya","year":"2000","journal-title":"Curr Opin Neurobiol"},{"issue":"4","key":"2021120108064581200_fcab266-B45","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1159\/000070199","article-title":"\u2018Speech initiation hesitation\u2019 following subthalamic nucleus stimulation in a patient with Parkinson\u2019s disease","volume":"49","author":"Moretti","year":"2003","journal-title":"Eur Neurol"},{"issue":"2","key":"2021120108064581200_fcab266-B46","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/s00702-008-0173-x","article-title":"Acquired stuttering after pallidal deep brain stimulation for dystonia","volume":"116","author":"Nebel","year":"2009","journal-title":"J Neural Transm"},{"issue":"5","key":"2021120108064581200_fcab266-B47","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1007\/s00702-010-0380-0","article-title":"Stuttering induced by thalamic deep brain stimulation for dystonia","volume":"117","author":"Allert","year":"2010","journal-title":"J Neural Transm"},{"issue":"1","key":"2021120108064581200_fcab266-B48","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/S0093-934X(75)80056-3","article-title":"Memory and perceptual deficits during electrical stimulation in the left and right thalamus and parietal subcortex","volume":"2","author":"Fedio","year":"1975","journal-title":"Brain Lang"},{"issue":"4","key":"2021120108064581200_fcab266-B49","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1093\/brain\/94.4.669","article-title":"Speech representation in ventrolateral thalamus","volume":"94","author":"Ojemann","year":"1971","journal-title":"Brain"},{"key":"2021120108064581200_fcab266-B50","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.bandl.2015.01.012","article-title":"Reduced fractional anisotropy in the anterior corpus callosum is associated with reduced speech fluency in persistent developmental stuttering","volume":"143","author":"Civier","year":"2015","journal-title":"Brain Lang"},{"issue":"4","key":"2021120108064581200_fcab266-B51","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/j.jcomdis.2011.03.001","article-title":"Corpus callosum differences associated with persistent stuttering in adults","volume":"44","author":"Choo","year":"2011","journal-title":"J Commun Disord"},{"issue":"4","key":"2021120108064581200_fcab266-B52","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1016\/j.neuroimage.2010.05.011","article-title":"A study of the reproducibility and etiology of diffusion anisotropy differences in developmental stuttering: A potential role for impaired myelination","volume":"52","author":"Cykowski","year":"2010","journal-title":"Neuroimage"},{"issue":"35","key":"2021120108064581200_fcab266-B53","doi-asserted-by":"crossref","first-page":"17515","DOI":"10.1073\/pnas.1901480116","article-title":"Human GNPTAB stuttering mutations engineered into mice cause vocalization deficits and astrocyte pathology in the corpus callosum","volume":"116","author":"Han","year":"2019","journal-title":"Proc Natl Acad Sci"},{"issue":"16","key":"2021120108064581200_fcab266-B54","doi-asserted-by":"crossref","first-page":"4522","DOI":"10.1523\/JNEUROSCI.3850-14.2016","article-title":"The contribution of the corpus callosum to language lateralization","volume":"36","author":"Hinkley","year":"2016","journal-title":"J Neurosci"}],"container-title":["Brain Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/braincomms\/advance-article-pdf\/doi\/10.1093\/braincomms\/fcab266\/41154037\/fcab266.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/braincomms\/article-pdf\/3\/4\/fcab266\/41365072\/fcab266.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/braincomms\/article-pdf\/3\/4\/fcab266\/41365072\/fcab266.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,12]],"date-time":"2023-11-12T12:18:47Z","timestamp":1699791527000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/braincomms\/article\/doi\/10.1093\/braincomms\/fcab266\/6427624"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,1]]},"references-count":54,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2021,10,1]]}},"URL":"https:\/\/doi.org\/10.1093\/braincomms\/fcab266","relation":{},"ISSN":["2632-1297"],"issn-type":[{"value":"2632-1297","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,10,1]]},"published":{"date-parts":[[2021,10,1]]},"article-number":"fcab266"}}