Abstract
ABSTRACTHomozygous STAT5B mutations causing growth hormone insensitivity with immune dysfunction were described in 10 patients since 2003, including two Brazilian brothers from the south of Brazil. Our objectives were to evaluate the prevalence of their STAT5B mutation in this region and to analyze the presence of a founder effect. We obtained DNA samples from 1,205 local inhabitants, 48 relatives of the homozygous patients and four individuals of another affected family. Genotyping for STAT5B c.424_427del mutation and for two polymorphic markers around it was done through fragment analysis technique. We also determined Y-chromosome and mtDNA haplotypes and genomic ancestry in heterozygous carriers. We identified seven families with STAT5B c.424_427del mutation, with 33 heterozygous individuals. The minor allelic frequency of this mutation was 0.29% in this population (confidence interval 95% 0.08-0.5%), which is significantly higher than the frequency of other pathogenic STAT5B allele variants observed in public databases (p < 0.001). All heterozygous carriers had the same haplotype present in the homozygous patients, found in only 9.4% of non-carriers (p < 0.001), supporting the existence of a founder effect. The Y-chromosome haplotype, mtDNA and genomic ancestry analysis indicated a European origin of this mutation. Our results provide compelling evidence for a founder effect of STAT5B c.424_427del mutation.
Highlights
STAT5B (OMIM 604260) is a key protein in the signaling pathway of substances that activate type I class cytokine receptors, such as growth hormone (GH), prolactin and interleukin 2 (IL2)
Homozygous mutations in STAT5B gene cause growth hormone insensitivity (Hwa et al, 2011; Scalco et al, 2013), a syndrome characterized by the inability of target tissues to respond to growth hormone
Since the first case report in 2003, a total of ten patients homozygous for seven different mutations in STAT5B were described (Kofoed et al, 2003; Hwa et al, 2005, 2007; Bernasconi et al, 2006; Vidarsdottir et al, 2006; Pugliese-Pires et al, 2010; Scaglia et al, 2012), including two Brazilian brothers homozygous for STAT5B c.424_427del mutation (Pugliese-Pires et al, 2010). These brothers were born at Criciúma, a city located in the south of Brazil, with an estimated population of 204,667 individuals according to the Brazilian Institute of Geography and Statistics (IBGE) 2014 census
Summary
STAT5B (OMIM 604260) is a key protein in the signaling pathway of substances that activate type I class cytokine receptors, such as growth hormone (GH), prolactin and interleukin 2 (IL2). Since the first case report in 2003, a total of ten patients homozygous for seven different mutations in STAT5B were described (Kofoed et al, 2003; Hwa et al, 2005, 2007; Bernasconi et al, 2006; Vidarsdottir et al, 2006; Pugliese-Pires et al, 2010; Scaglia et al, 2012), including two Brazilian brothers homozygous for STAT5B c.424_427del mutation (Pugliese-Pires et al, 2010) These brothers were born at Criciúma, a city located in the south of Brazil (at 28°40’39” S 49°22’11” W), with an estimated population of 204,667 individuals according to the Brazilian Institute of Geography and Statistics (IBGE) 2014 census. They reported that an unrelated family in the same city had two kids with similar clinical findings, deceased as a consequence of respiratory failure
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