title: 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.
authors.affiliation: Laboratório de Imunohematologia e Hematologia Forense (LIM40), Departamento de Medicina Legal, Ética Médica e Medicina Social e do Trabalho, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Fernanda T
authors.initials: FT
authors.lastname: Gonçalves
authors.forename: Cintia
authors.initials: C
authors.lastname: Fridman
authors.forename: Emília M
authors.initials: EM
authors.lastname: Pinto
authors.forename: Jaime
authors.initials: J
authors.lastname: Guevara-Aguirre
authors.forename: Orit
authors.initials: O
authors.lastname: Shevah
authors.forename: Arlan L
authors.initials: AL
authors.lastname: Rosembloom
authors.forename: Vivian
authors.initials: V
authors.lastname: Hwa
authors.forename: Fernando
authors.initials: F
authors.lastname: Cassorla
authors.forename: Ron G
authors.initials: RG
authors.lastname: Rosenfeld
authors.forename: Theresa S S
authors.initials: TS
authors.lastname: Lins
authors.forename: Durval
authors.initials: D
authors.lastname: Damiani
authors.forename: Ivo J P
authors.initials: IJ
authors.lastname: Arnhold
authors.forename: Zvi
authors.initials: Z
authors.lastname: Laron
authors.forename: Alexander A L
authors.initials: AA
authors.lastname: Jorge
mesh_terms: D001938:Brazil; D041322:Chromosomes, Human, Y; D004272:DNA, Mitochondrial; D004484:Ecuador; D005260:Female; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D007557:Israel; D007585:Jews / Q000235:genetics; D046150:Laron Syndrome / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation; D022821:RNA Splice Sites; D011986:Receptors, Somatotropin / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D022821:RNA Splice Sites; D011986:Receptors, Somatotropin
keywords: Laron syndrome; Y-chromosome haplogroups; growth hormone insensitivity; growth hormone receptor; growth hormone receptor deficiency; lineage markers; mitochondrial haplogroups