Identifying Quantitative Trait Loci Affecting Resistance to Congenital Hypothyroidism in 129+Ter/SvJcl Strain Mice

• Published in: PloS one Vol. 7; no. 1; p. e31035
• Main Authors: Hosoda, Yayoi, Sasaki, Nobuya, Kameda, Yayoi, Torigoe, Daisuke, Agui, Takashi
• Format: Journal Article
• Language: English
• Published: San Francisco Public Library of Science 27.01.2012
• Subjects: Alleles; Biology; Congenital diseases; Dwarfism; Growth rate; Hypoplasia; Hypothyroidism; Kinases; Loci; Medicine; Mice; Mutation; Organogenesis; Quantitative trait loci; Signaling; Sulfation; Sulfotransferase; Thyroid; Thyroid diseases; Thyroid-stimulating hormone; Thyroid-stimulating hormone receptors; Tyrosine; Veterinary colleges; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0031035

Tyrosylprotein sulfotransferase 2 (TPST2) is one of the enzymes responsible for tyrosine O-sulfation and catalyzes the sulfation of the specific tyrosine residue of thyroid stimulating hormone receptor (TSHR). Since this modification is indispensable for the activation of TSH signaling, a non-functional TPST2 mutation (Tpst2grt) in DW/J-grt mice leads to congenital hypothyroidism (CH) characterized by severe thyroid hypoplasia and dwarfism related to TSH hyporesponsiveness. Previous studies indicated that the genetic background of the 129+Ter/SvJcl (129) mouse strain ameliorates Tpst2grt-induced CH. To identify loci responsible for CH resistance in 129 mice, we performed quantitative trait locus (QTL) analysis using backcross progenies from susceptible DW/J and resistant 129 mice. We used the first principal component calculated from body weights at 5, 8 and 10 weeks as an indicator of CH, and QTL analysis mapped a major QTL showing a highly significant linkage to the distal portion of chromosome (Chr) 2; between D2Mit62 and D2Mit304, particularly close to D2Mit255. In addition, two male-specific QTLs showing statistically suggestive linkage were also detected on Chrs 4 and 18, respectively. All QTL alleles derived from the 129 strain increased resistance to growth retardation. There was also a positive correlation between recovery from thyroid hypoplasia and the presence of the 129 allele at D2Mit255 in male progenies. These results suggested that the major QTL on Chr 2 is involved in thyroid development. Moreover, since DW/J congenic strain mice carrying both a Tpst2grt mutation and 129 alleles in the major QTL show resistance to dwarfism and thyroid hypoplasia, we confirmed the presence of the resistant gene in this region, and that it is involved in thyroid development. Further genetical analysis should lead to identification of genes for CH tolerance and, from a better understanding of thyroid organogenesis and function, the subsequent development of new treatments for thyroid disorders.