The E180splice mutation in the GHR gene causing Laron syndrome: Witness of a Sephardic Jewish exodus from the Iberian Peninsula to the New World?

Abstract

Laron syndrome (LS) is a genetic disorder caused by mutations in the growth hormone receptor (GHR) gene. The most frequent GHR mutation is E180splice (rs121909360), which was initially found in an inbred population of Spanish descent in Ecuador and subsequently in Israel, Brazil, Chile, and the United States. The aim of the present study is to determine if the E180splice mutation arose from a common origin. We studied 22 patients with LS from Ecuador, Israel (of Moroccan origin), Brazil, Chile, and the United States (of Mexican origin) who were homozygous for the E180splice mutation and compared them to control individuals for markers surrounding the GHR, intragenic polymorphisms, and Y-chromosome STR. An identical haplotype was found in all but one of the subjects carrying the E180splice mutation: D5S665: 150/150; D5S2082: 192/192; D5S2087: 246/246; rs6179 G/G; and rs6180 C/C. One patient differed from the others only at D5S2082 (168/192). This haplotype is rare (~1%) in control individuals and confirmed that the E180splice-associated haplotype was not derived from independent origins but represented recombination from a common ancestor. The analysis of paternal lineage markers showed that 50% belong to haplogroup R1b (found in Portugal and Spain) and 40% to haplogroups J and E (typical in the Middle East and in Eastern European Jews). The germline E180Splice mutation appears to have originated from a single common ancestor. The presence of Y-chromosome markers associated with Sephardic populations in persons harboring the E180splice mutation provides genetic evidence in support of the historical tracking of the exodus of this specific population.

Characterization of four Latin American families confirms previous findings and reveals novel features of acid‐labile subunit deficiency

“…The finding of a similar haplotype with nine intragenic SNPs and two flanking microsatellites suggests a gene‐founder effect with likely a common ancestor from Spain. A similar finding of a common ancestor has been reported for the E180 splice variant in the GHR gene in patients with Laron syndrome from different countries …”

“…The finding of a similar haplotype with nine intragenic SNPs and two flanking microsatellites suggests a genefounder effect with likely a common ancestor from Spain. A similar finding of a common ancestor has been reported for the E180 splice variant in the GHR gene in patients with Laron syndrome from different countries 15. The auxological evaluation and the characterization of the IGF system in all eight ACLSD subjects, fourteen HC and three WT relatives revealed that HC for pathogenic IGFALS variants were 0.6 SD shorter than WT, presenting IGF-I, IGFBP-3 and ALS levels intermediate between ACLSD and WT relatives.…”

Targeted Resequencing of Putative Growth-Related Genes Using Whole Exome Sequencing in Patients with Severe Primary IGF-I Deficiency

“…Two siblings (patients 20 and 21) suffered from a previously described truncating variant of the GH receptor, which has been described as leading in an unstable receptor expression [22]. Furthermore, we found a novel missense variant in IGF2 (p.Arg156Cys) in a putatively affected father and his affected daughter (patient 7), which was classified as variant of uncertain clinical significance.…”

Growth Hormone insensitivity (Laron syndrome): Report of a new family and review of Brazilian patients

“…In Brazil, 19 patients with LS have been reported so far. Most of them carry the E180 splice mutation (c.594A>G, p.V199_M208 del; rs121909360) (Jorge et al, 2005;Goncalves et al, 2014). In this report, two sibs from a consanguineous family, with a mutation in the exon 2 of GHR, are described.…”