title: MCT8 mutation analysis and identification of the first female with Allan-Herndon-Dudley syndrome due to loss of MCT8 expression.
abstract: Mutations in the thyroid monocarboxylate transporter 8 gene (MCT8/SLC16A2) have been reported to result in X-linked mental retardation (XLMR) in patients with clinical features of the Allan-Herndon-Dudley syndrome (AHDS). We performed MCT8 mutation analysis including 13 XLMR families with LOD scores >2.0, 401 male MR sibships and 47 sporadic male patients with AHDS-like clinical features. One nonsense mutation (c.629insA) and two missense changes (c.1A>T and c.1673G>A) were identified. Consistent with previous reports on MCT8 missense changes, the patient with c.1673G>A showed elevated serum T3 level. The c.1A>T change in another patient affects a putative translation start codon, but the same change was present in his healthy brother. In addition normal serum T3 levels were present, suggesting that the c.1A>T (NM_006517) variation is not responsible for the MR phenotype but indicates that MCT8 translation likely starts with a methionine at position p.75. Moreover, we characterized a de novo translocation t(X;9)(q13.2;p24) in a female patient with full blown AHDS clinical features including elevated serum T3 levels. The MCT8 gene was disrupted at the X-breakpoint. A complete loss of MCT8 expression was observed in a fibroblast cell-line derived from this patient because of unfavorable nonrandom X-inactivation. Taken together, these data indicate that MCT8 mutations are not common in non-AHDS MR patients yet they support that elevated serum T3 levels can be indicative for AHDS and that AHDS clinical features can be present in female MCT8 mutation carriers whenever there is unfavorable nonrandom X-inactivation.
authors.affiliation: Department of Clinical Genetics, University Hospital azM Maastricht, Maastricht, The Netherlands. suzanne.frints@gen.unimaas.nl
authors.forename: Suzanna Gerarda Maria
authors.initials: SG
authors.lastname: Frints
authors.forename: Steffen
authors.initials: S
authors.lastname: Lenzner
authors.forename: Mareike
authors.initials: M
authors.lastname: Bauters
authors.forename: Lars Riff
authors.initials: LR
authors.lastname: Jensen
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.forename: Vincent
authors.initials: V
authors.lastname: des Portes
authors.forename: Ute
authors.initials: U
authors.lastname: Moog
authors.forename: Merryn Victor Erik
authors.initials: MV
authors.lastname: Macville
authors.forename: Kees
authors.initials: K
authors.lastname: van Roozendaal
authors.forename: Constance Theresia Rimbertha Maria
authors.initials: CT
authors.lastname: Schrander-Stumpel
authors.forename: Andreas
authors.initials: A
authors.lastname: Tzschach
authors.forename: Peter
authors.initials: P
authors.lastname: Marynen
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.forename: Ben
authors.initials: B
authors.lastname: Hamel
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.forename: Chérif
authors.initials: C
authors.lastname: Beldjord
authors.forename: Gillian
authors.initials: G
authors.lastname: Turner
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
authors.forename: Claude
authors.initials: C
authors.lastname: Moraine
authors.forename: Martine
authors.initials: M
authors.lastname: Raynaud
authors.forename: Hans Hilger
authors.initials: HH
authors.lastname: Ropers
authors.forename: Guy
authors.initials: G
authors.lastname: Froyen
authors.forename: Andreas Walter
authors.initials: AW
authors.lastname: Kuss
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology; D000293:Adolescent; D000328:Adult; D002675:Child, Preschool; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D041321:Chromosomes, Human, X / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D038901:X-Linked Intellectual Disability / Q000097:blood / Q000235:genetics* / Q000473:pathology; D027501:Monocarboxylic Acid Transporters / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D010375:Pedigree; D027981:Symporters; D013577:Syndrome; D013974:Thyroxine / Q000097:blood; D014178:Translocation, Genetic / Q000235:genetics; D014284:Triiodothyronine / Q000097:blood; D049951:X Chromosome Inactivation / Q000235:genetics
chemical_list: D027501:Monocarboxylic Acid Transporters; C090735:SLC16A2 protein, human; D027981:Symporters; D014284:Triiodothyronine; D013974:Thyroxine