A Novel Syndrome Combining Thyroid and Neurological Abnormalities Is Associated with Mutations in a Monocarboxylate Transporter Gene Alexandra M. Dumitrescu,

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A Novel Syndrome Combining Thyroid and Neurological Abnormalities Is Associated with Mutations in a Monocarboxylate Transporter Gene Alexandra M. Dumitrescu, Xiao-Hui Liao, Thomas B. Best, Knut Brockmann, Samuel Refetoff The American Journal of Human Genetics Volume 74, Issue 1, Pages 168-175 (January 2004) DOI: 10.1086/380999 Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 1 Family Ro. A, Pedigree and thyroid function tests. Values above the upper limit of normal are shown in red, and those below the lower limit of normal are in blue. TT4 = total T4; TT3 = total T3; TrT3 = total reverse T3; FT4I = free T4 index; TSH = thyroid stimulating hormone; AITD = autoimmune thyroid disease; MCT8 = monocarboxylate transporter 8. B, Electropherograms showing the mutation found in exon 5 of MCT8 in the propositus (top tracing) and the corresponding normal sequence (bottom tracing). C, Results of genotyping of all family members for the mutation shown in B. A 530-bp fragment, amplified by PCR and containing sequences of the WT exon 5, produces two bands, 327 bp and 203 bp, when digested with HpaII. The mutant allele has a new HpaII restriction site producing two additional bands, 235 bp and 92 bp (latter band not shown), by further digestion of the 327-bp fragment. This occurs in the hemizygous propositus and the heterozygous mother. D, The inheritance pattern of the MCT8 locus on chromosome X, investigated using polymorphic markers in the vicinity of MCT8. Three alleles are identified in the grandparents of the propositus. The affected allele transmitted from the mother is shown in red. The American Journal of Human Genetics 2004 74, 168-175DOI: (10.1086/380999) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 2 Family Fi. A, Pedigree and thyroid function tests. For details and abbreviations, see the legend to figure 1. B, Electropherograms showing the WT reverse sequence from part of exon 3 of the MCT8 gene (upper tracing), the location of the nucleotide deletion in the propositus (middle tracing), and the sequence of the heterozygous mother (lower tracing). C, Results of genotyping of all family members for the mutation shown in B. The 178-bp product amplified from the mutant allele is digested into two fragments of 101 bp and 77 bp by HhaI, whereas the WT allele remains intact. Complete digestion is observed in the two hemizygous affected males (II4 and III1). The heterozygous females (I2, II2, and II3) show three bands: the 179-bp fragment representing the WT allele and the two smaller fragments representing the digested mutant allele. The American Journal of Human Genetics 2004 74, 168-175DOI: (10.1086/380999) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 3 Graphic representation of thyroid function tests in the members of the two families. The gray interval denotes the normal range for each determination. Note that values of affected hemizygous males are outside the normal range for all tests, whereas those of heterozygous females are, in general, intermediate to the unaffected subjects and affected hemizygotes. The American Journal of Human Genetics 2004 74, 168-175DOI: (10.1086/380999) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 4 X-inactivation assay using a polymorphic repeat in the AR gene. Gels are aligned with the corresponding members on the pedigrees. For each individual lane, a dash represents the PCR product of mock digested gDNA (no enzyme added), and “H” denotes the PCR product using the HhaI-digested gDNA as the template. As expected, no product is obtained using HhaI-digested gDNA from males, since their X-chromosome allele is active and unmethylated. A, Family Ro. Three X-chromosome alleles are identified in the grandparents of the propositus: alleles 1 and 3 are from the grandmother, and allele 2 is deduced as originating from the deceased grandfather and is shared by his three daughters (all females of generation II). The pattern of bands seen in the H lane for the females, even though not quantitative, is suggestive of no preferential X inactivation of the two alleles. B, Family Fi. The grandmother is homozygous for the polymorphic repeat in exon 1 of the AR gene, and analysis is therefore uninformative. However, the other two informative females show no preferential X inactivation of the two alleles. The American Journal of Human Genetics 2004 74, 168-175DOI: (10.1086/380999) Copyright © 2004 The American Society of Human Genetics Terms and Conditions