Homozygous HLA‐G*0105N healthy individuals indicate that membrane‐anchored HLA‐G1 molecule is not necessary for survival

Abstract

HLA-G is expected to play an important role during fetal development. Recently, a healthy individual homozygous for the HLA-G*0105N allele has been described, suggesting that HLA-G expression was not essential for fetal survival. We now report studies of one family with five healthy siblings homozygous for HLA-G*0105N, who had been normally delivered; three of these siblings were females who also had normal deliveries. In addition, HLA-G*0105N cDNA has been fully sequenced, and normal G1 membrane anchored protein cannot be translated since after the codon 130 cytosine deletion (exon 3) a reading frameshift is observed leading to the existence of premature stop codon at position 189 (beginning of exon 4). Other protein isoforms (G2, G3 and G6), all containing the leader peptide and the alpha1 domain, are possible and their messenger mRNAs were found; any of these may undertake the necessary HLA-G functions. Our data show that the membrane anchored HLA-G molecule is not necessary in either mother or fetus for a normal pregnancy and survival. Also, individuals homozygous for HLA-G*0105N are healthy and with no indications of immunodeficiency or autoimmunity.

Recognition of HLA‐G by the NK cell receptor KIR2DL4 is not essential for human reproduction

“…Previous description of adult individuals homozygous for mutations that prevent expression of HLA-G1 raised concern on the role of this MHC molecule in promoting maternal-fetal tolerance [42,43]. It was subsequently proposed that other HLA-G isoforms produced by alternative splicing of the mutant allele could be recognized by KIR2DL4 and inhibit maternal NK cells [44].…”

How Micrornas Affect the Expression of Human Leukocyte Antigeng in Pregnancy

“…Consequently, there will be incomplete formation of HLA-G1, -G4 and -G5 but not of the isoforms that do not contain the α2 region (Discorde et al, 2005;Ober et al, 1998). Remarkably, individuals homozygous for the HLA-G*01:05N mutation are still able to have a term pregnancy without the presence of three different isoforms (Casro et al, 2000;Ober et al, 1998). Indeed, Discorde and coworkers have confirmed the suggestion that other isoforms can compensate for the loss of HLA-G1,-G4 and-G5 and they have proven to be redundant in homozygous individuals (Discorde et al, 2005).…”

HLA-G: Su importancia inmunológica

“…En contraste con el extensivo polimorfismo de los genes clase I clásicos del HLA, se ha considerado bajo el grado de polimorfismo en el locus del HLA-G, presentando una limitada heterogeneidad de secuencias y con pocos alelos descritos (6,(11)(12)(13)(14)(15)(16)(17)(18).…”

“…No ha sido encontrado en poblaciones caucásicas Americanas o Japonesas (11,13). La descripción de individuos sanos homocigotos para el alelo G*0105N indica que el HLA-G1 no es necesario para la supervivencia fetal (14,15). Sin embargo, Van der Ven y Ober en 1997 demostraron por análisis de secuencias en el exón 2 y 3 un extensivo polimorfismo del locus HLA-G en mujeres africanas no emparentadas (12,16).…”

“…El HLA-E está involucrado en la regulación positiva y negativa de citotoxicidad de las NK (11,28,29). Rouas-Freiss y colaboradores encontraron que la transfección de las isoformas truncadas HLA-G2, -G3 y -G4 pueden inhibir la actividad lítica de las NK, esto podría ser muy importante durante los procesos patológicos y fisiológicos en los cuales las expresión del HLA-G1 se encuentre alterada (15,23).…”