title: Association between Rare Variants in AP4E1, a Component of Intracellular Trafficking, and Persistent Stuttering.
abstract: Stuttering is a common, highly heritable neurodevelopmental disorder characterized by deficits in the volitional control of speech. Whole-exome sequencing identified two heterozygous AP4E1 coding variants, c.1549G>A (p.Val517Ile) and c.2401G>A (p.Glu801Lys), that co-segregate with persistent developmental stuttering in a large Cameroonian family, and we observed the same two variants in unrelated Cameroonians with persistent stuttering. We found 23 other rare variants, including predicted loss-of-function variants, in AP4E1 in unrelated stuttering individuals in Cameroon, Pakistan, and North America. The rate of rare variants in AP4E1 was significantly higher in unrelated Pakistani and Cameroonian stuttering individuals than in population-matched control individuals, and coding variants in this gene are exceptionally rare in the general sub-Saharan West African, South Asian, and North American populations. Clinical examination of the Cameroonian family members failed to identify any symptoms previously reported in rare individuals carrying homozygous loss-of-function mutations in this gene. AP4E1 encodes the ε subunit of the heterotetrameric (ε-β4-μ4-σ4) AP-4 complex, involved in protein sorting at the trans-Golgi network. We found that the μ4 subunit of AP-4 interacts with NAGPA, an enzyme involved in the synthesis of the mannose 6-phosphate signal that targets acid hydrolases to the lysosome and the product of a gene previously associated with stuttering. These findings implicate deficits in intracellular trafficking in persistent stuttering.
authors.affiliation: National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA.
authors.forename: M Hashim
authors.initials: MH
authors.lastname: Raza
authors.affiliation: Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Mattera
authors.affiliation: National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Morell
authors.affiliation: National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Sainz
authors.affiliation: National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Rahn
authors.affiliation: National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Gutierrez
authors.affiliation: National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Paris
authors.affiliation: National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Root
authors.affiliation: Clinical Center Speech Language Pathology Service, NIH, Bethesda, MD 20892, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Solomon
authors.affiliation: National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA.
authors.forename: Carmen
authors.initials: C
authors.lastname: Brewer
authors.affiliation: Institute of Chemistry, University of the Punjab, Lahore 54590, Pakistan.
authors.forename: M Asim Raza
authors.initials: MA
authors.lastname: Basra
authors.affiliation: Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 53700, Pakistan.
authors.forename: Shaheen
authors.initials: S
authors.lastname: Khan
authors.affiliation: Alama Iqbal Medical Research Center, Lahore 54550, Pakistan.
authors.forename: Sheikh
authors.initials: S
authors.lastname: Riazuddin
authors.affiliation: National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA.
authors.forename: Allen
authors.initials: A
authors.lastname: Braun
authors.affiliation: Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA.
authors.forename: Juan S
authors.initials: JS
authors.lastname: Bonifacino
authors.affiliation: National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA. Electronic address: drayna@nidcd.nih.gov.
authors.forename: Dennis
authors.initials: D
authors.lastname: Drayna
mesh_terms: D033964:Adaptor Protein Complex 4 / Q000235:genetics*; D044466:Asian People; D016022:Case-Control Studies; D005260:Female; D005500:Follow-Up Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D011379:Prognosis; D021381:Protein Transport / Q000235:genetics*; D013342:Stuttering / Q000235:genetics* / Q000473:pathology*; D021601:trans-Golgi Network
chemical_list: D033964:Adaptor Protein Complex 4; D010727:Phosphoric Diester Hydrolases; C026645:N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase