Identification of limb-specific Lmx1b auto-regulatory modules with Nail-patella syndrome pathogenicity.

LMX1B haploinsufficiency causes Nail-patella syndrome (NPS; MIM 161200), characterized by nail dysplasia, absent/hypoplastic patellae, chronic kidney disease, and glaucoma. Accordingly in mice, Lmx1b has been shown to play crucial roles in the development of the limb, kidney and eye. Although one functional allele of Lmx1b appears adequate for development, Lmx1b null mice display ventral-ventral distal limbs with abnormal kidney, eye and cerebellar development, more disruptive, but fully concordant with NPS. In Lmx1b functional knockouts (KOs), Lmx1b transcription in the limb is decreased nearly 6-fold, indicating autoregulation. Herein, we report on two conserved Lmx1b-associated cis-regulatory modules (LARM1 and LARM2) that are bound by Lmx1b, amplify Lmx1b expression with unique spatial modularity in the limb, and are necessary for Lmx1b-mediated limb dorsalization. These enhancers, being conserved across vertebrates (including coelacanth, but not other fish species), and required for normal locomotion, provide a unique opportunity to study the role of dorsalization in the fin to limb transition. We also report on two NPS patient families with normal LMX1B coding sequence, but with loss-of-function variations in the LARM1/2 region, stressing the role of regulatory modules in disease pathogenesis.

Actualidad del diagnóstico genético preimplantacional (DGP) en el laboratorio de FIV / News of the preimplantational genetic diagnosis (DGP) in the IVF laboratory

La actualidad del diagnóstico genético preimplantacional (DGP) se encuentra íntimamente ligada a la evolución de la genética molecular, cuyo desarrollo nos ha permitido realizar diagnósticos, cada vez más precisos, en el embrión humano. Son varios los puntos en los que existen controversias. Por un lado no existe consenso sobre el día en el que debemos realizar la biopsia embrionaria. El estudio genético debe realizarse mediante la utilización de una técnica que estudie la totalidad de la dotación cromosómica del embrión (aCGH, NGS. . ). También existe duda sobre cual es el último estadío embrionario en el que se pueden producir errores mitóticos y añadimos el pensamiento relativo a que lo que estudiamos, tanto biopsiando en día +3 como en día +5/6 tal vez no constituya finalmente el embrión, luego no sea suficientemente representativo del mismo. Entendemos que el SGP es un procedimiento más de selección embrionaria, al igual que la morfología, la morfocinética y el crecimiento a blastocisto. La combinación de los tres puede aumentar la posibilidad de éxito en aquellas situaciones en las que hay un número suficiente de embriones, pero pensamos que hay que demostrar su verdadera eficiencia con estudios más amplios

The relevance of preimplantation genetic diagnosis (PGD) is closely linked to the evolution of molecular genetics, whose development has allowed us to make diagnoses, more and more precise, in the human embryo. There are several points where there are controversies. On the one hand there is no consensus on the day in which we must perform the embryo biopsy. The genetic study must be carried out by using a technique that studies the entire chromosomal envelope of the embryo (aCGH, NGS . . ). There is also doubt about which is the last embryonic stage in which mitotic errors can occur and we add the thought that what we study, both biopsy on day +3 and day +5/6 may not be the embryo finally, then it is not sufficiently representative of it. We understand that the SGP is a procedure for embryo selection, as well as morphology, morphokinetics and blastocyst growth. The combination of the three can increase the possibility of success in those situations in which there is a sufficient number of embryos, but we think that its true efficiency must be demonstrated with broader studies