Generalized thyroid hormone resistance: identification of an arginine to cystine mutation in codon 315 of the c-erb A beta thyroid hormone receptor.
The present report studies a large kindred (WR) with generalized thyroid hormone resistance that has varying degrees of neuropsychological dysfunction, hyperactivity, poor attention span, decreased IQ and/or abnormalities in spatial perception. In this kindred, there has been found tight linkage of the syndrome with the c-erb A beta gene. The present study was performed to identify the presence of a possible gene mutation as a cause for this syndrome. DNA from peripheral leukocytes was isolated from 15 unaffected and 8 affected individuals from the kindred. Primers encompassing exons 9 (nucleotides 1171-1429) and 10 (nucleotides 1430-1698) were synthesized and used in PCR reactions to amplify these exons. Direct sequencing revealed a consistent substitution in each affected subject, but in none of the unaffected individuals, of a C to T change in one allele from nucleotide 1243, resulting in an arg to cys change in codon 315. The mutant and wild-type human beta 1 receptors were prepared and their translated proteins were analyzed for T3 binding. The WR T3 receptor from affected patients had reduced T3 binding affinity, with values approximately 2.5 x 10(10) M-1 compared to about 5 x 10(10) M-1 in normals. In summary, we have: i) identified a consistent and reproducible mutation of a C to T change in nucleotide 1243 in each of the affected but in none of the unaffected individuals of a large well characterized kindred with generalized thyroid hormone resistance; and ii) noted that the WR allele causes an approximate 50% decrease in the T3 binding affinity.(ABSTRACT TRUNCATED AT 250 WORDS)
Burman
K D
KD
Department of Medicine, Walter Reed Army Medical Center, Washington, DC 20307.
Djuh
Y Y
YY
Nicholson
D
D
Rhooms
P
P
Wartofsky
L
L
Fein
H G
HG
Usala
S J
SJ
Hao
E H
EH
Bradley
W E
WE
Berard
J
J
D001120:Arginine / Q000235:genetics*; D001483:Base Sequence; D003062:Codon; D003553:Cystine / Q000235:genetics*; D004247:DNA / Q000737:chemistry; D015252:Deoxyribonucleases, Type II Site-Specific; D004351:Drug Resistance; D008040:Genetic Linkage; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011988:Receptors, Thyroid Hormone / Q000235:genetics* / Q000378:metabolism; D013577:Syndrome; D013963:Thyroid Hormones; D014284:Triiodothyronine / Q000378:metabolism
D003062:Codon; D011518:Proto-Oncogene Proteins; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; D014284:Triiodothyronine; D003553:Cystine; D004247:DNA; D001120:Arginine; D015252:Deoxyribonucleases, Type II Site-Specific; C037130:GCGC-specific type II deoxyribonucleases