Hallan una mutación genética que es capaz de causar y curar una enfermedad rara

Los errores durante la replicación de los genes son comunes durante la división celular y pueden causar numerosas enfermedades, incluido el cáncer. Los científicos de la Facultad de Medicina de la Universidad de Yale (Estados Unidos) han descubierto un fenómeno mucho más raro con potenciales aplicaciones terapéuticas: un grupo de genes que provocan el desarrollo de una enfermedad rara pero que, al mismo tiempo, muestran una gran capacidad para reparar ese mismo trastorno.

El hallazgo ha sido publicado este jueves en la revista 'Science' y describe cómo una copia mutada del gen 'Queratina 10' causa una grave enfermedad rara de origen dermatológico llamada 'ictiosis en confeti'. Sin embargo, entre la piel afectada y escamosa, los pacientes afectados por este trastorno tienen de cientos a miles de 'motas' de piel sana.

Este fenómeno, explican los investigadores de Yale, ocurre por la recombinación de cromosomas previa a división celular. En lugar de producir una copia normal de la gen y una dominante, la mutación responsable de la enfermedad hace que el intercambio entre los cromosomas derive en células con dos copias alteradas o con dos copias sanas. Esto provoca que, más tarde, en la piel aparezcan motas de piel sana causadas por células libre de enfermedad.

"Lo normal es que, si se tiene una mutación genética que provoca una enfermedad, se cargue con ella y se siga reproduciendo, pero se ha demostrado que en esta enfermedad aparece, inusualmente y con una alta intensidad, copias de genes libres de mutaciones en las células", explica el primer autor del estudio y profesor asistente de Dermatología en Yale, Keith Choate.

"La razón por la que estas mutaciones en particular se convierten en células sanas con tanta frecuencia no está muy clara", afirman Choate. No obstante, se ha detectado que en todos los pacientes afectados por esta enfermedad la proteína situada en la parte final de la 'Queratina 10' es reemplazada por una secuencia de nuevas proteínas enriquecidas por un aminoácido denominado arginina.

Esto hace que la parte mutada de la 'Queratina 10' se sitúe en la parte equivocada de la célula. "Creemos que esta colocación errónea en el gen contribuye tanto a la severidad de la enfermedad como a la aparición de replicaciones de piel sana y normal", añade Richard Lifton, catedrático del Departamento de Genética de esta universidad estadounidense y co-autor del estudio.

En este sentido, los investigadores apuntan que el conocimiento de estas mutaciones particulares que se replican con alta frecuencia ofrecen una nueva vía de investigación para mimetizar este proceso y desarrollar nuevos tratamientos para otras enfermedades de origen genético.

Researchers discover why some women are sub-fertile and have a poor response to ovarian stimulating hormones

Researchers have discovered that some women carry a genetic variation that makes them sub-fertile and less likely to respond to ovarian stimulating hormones during fertility treatment. The discovery opens the way to identifying these women and devising personalised fertility treatments that could bypass the problem caused by the genetic abnormality.
Dr Maria Lalioti told the 26th annual meeting of the European Society of Human Reproduction and Embryology in Rome today (Tuesday) that she and her colleagues from the Yale University Medical School, New Haven (USA), had found that some women had an abnormal hormone receptor on cells surrounding oocytes (eggs). This abnormal receptor impaired the function of normal receptors that were also present and resulted in the affected women responding less well to Follicle Stimulating Hormone (FSH), which is given to women during fertility treatment to stimulate the production of more than one oocyte.
Dr Lalioti, as assistant professor in the Department of Obstetrics Gynecology and Reproductive Sciences at Yale, said: "When a woman undergoes in vitro fertilisation, she receives medication called Follicle Stimulating Hormone to produce more than one oocyte, which is the normal production each month. Cells called granulosa cells, which surround the oocyte, receive the FSH; these cells excrete other factors that ‘feed’ the oocyte. The granulosa cells have proteins present on their surface called FSH receptors (or FSHR) and it is these proteins that stick to the FSH and then carry signals into the cell’s interior. When we looked at a portion of these granulosa cells in the laboratory we saw that in some women, who produced very few oocytes, there were some receptors that lacked a piece of the protein, although there were still other, normal FSHR in the women’s cells."
The abnormal FSHR contained a deleted sequence of protein called exon 2 that is an important part of the protein that binds the FSH; FSHR with the exon 2 deletion was only detected in women younger than 35 who had a poor response to FSH and yielded less than four oocytes in a follicle stimulating cycle.
"We produced the normal and abnormal protein in the lab in a different type of cell called HEK293 (Human Embryonic Kidney) which is a common cell type used in the labs to examine properties of proteins. We saw that when the abnormal receptor was present, the normal one could no longer work as well as it does when it is the only protein present," explained Dr Lalioti. "The receptor is normally present on the cell surface in order to meet and bind FSH, and it needs to go through a number of cellular checkpoints inside the cell that assure the quality of the protein presented on the surface. We saw that the abnormal receptor remains longer in one of these checkpoint compartments, indicating that the cell has detected a problem and is trying to correct it. In this way the abnormal FSHR can contribute to an abnormally low response to stimulation in certain women undergoing IVF."
Dr Lalioti’s discovery of the mechanism behind why some young women have a poor response to FSH has important implications for future research and treatment of these women. "The importance of this finding is that it creates a link between genetic variation and sub-fertility. These women have a normal menstrual cycle and they may present to the fertility centre as patients with unexplained infertility, before their first IVF cycle that would reveal an ovarian stimulation defect," she said.
"Our finding explains why these women have a lower response to FSH. Currently, FSH is the only medication used to stimulate ovarian response, but once other medications are available that can bypass the receptor for FSH, they can be tested on these women. Also, at present we cannot predict if the women would profit from having higher doses of medication, and, in fact, some preliminary data from other groups show the opposite: that lower FSH may be more beneficial."
Future research will examine the FSHR signalling mechanisms within the cell and investigate how newly developed drugs might bypass the problems created by the genetic abnormality. "In the future, this could lead to personalised treatments for a sub-group of patients," said Dr Lalioti.
It is not known how many women have this particular genetic variation. Dr Lalioti found it in two out of five women that she tested. "These patients are hard to recruit because most patients with a low response to FSH do not complete the IVF cycle for financial reasons," she said. "We need to recruit more patients to discover how common it is." She and her colleagues will need a year to recruit and test more women, to set up collaborations with more fertility centres and to start to test new drugs that could promote oocyte production more effectively in these women.