MCT8 mutation analysis and identification of the first female with Allan-Herndon-Dudley syndrome due to loss of MCT8 expression.
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.
Frints
Suzanna Gerarda Maria
SG
Department of Clinical Genetics, University Hospital azM Maastricht, Maastricht, The Netherlands. suzanne.frints@gen.unimaas.nl
Lenzner
Steffen
S
Bauters
Mareike
M
Jensen
Lars Riff
LR
Van Esch
Hilde
H
des Portes
Vincent
V
Moog
Ute
U
Macville
Merryn Victor Erik
MV
van Roozendaal
Kees
K
Schrander-Stumpel
Constance Theresia Rimbertha Maria
CT
Tzschach
Andreas
A
Marynen
Peter
P
Fryns
Jean-Pierre
JP
Hamel
Ben
B
van Bokhoven
Hans
H
Chelly
Jamel
J
Beldjord
Chérif
C
Turner
Gillian
G
Gecz
Jozef
J
Moraine
Claude
C
Raynaud
Martine
M
Ropers
Hans Hilger
HH
Froyen
Guy
G
Kuss
Andreas Walter
AW
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
D027501:Monocarboxylic Acid Transporters; C090735:SLC16A2 protein, human; D027981:Symporters; D014284:Triiodothyronine; D013974:Thyroxine