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GREENBERG DYSPLASIA Italian Version Gene Name: LBR Lamin B Receptor Localiza On

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GREENBERG DYSPLASIA Italian Version Gene Name: LBR Lamin B Receptor Localiza On GREENBERG DYSPLASIA Italian version Gene name: LBR Lamin B Receptor Localiza<on: Cytogene2c band: 1q42.12 – (reverse strand) Protein name: Lamin-B receptor Size: 615 amino acids Molecular mass: 70703 D Protein localizaon: inner core of the membrane and mul2-pass protein membrane K K THe protein is mostly present in the nucleus, in the inner core of the plasma membrane as mul2- pass protein membrane. Structure: Q14739 2DG: 62 aa THe Tudor domain that may not recognize methylation marks, but rather bind unassembled free Histone H3. Descripon and funcon THe protein encoded by this gene belongs to the ERG4/ERG24 family. It is located in the nuclear envelope inner membrane and ancHors the lamina and the HeterocHroma2n to the membrane. It may mediate interac2on between cHroma2n and lamin B. Muta<ons and disorders: THe lamin B receptor (LBR) is an inner nuclear membrane protein with a structural func2on interac2ng with cHroma2n and lamins, and an enzyma2c func2on as a sterol reductase. Heterozygous LBR muta2ons cause nuclear Hyposegmenta2on in neutropHils (Pelger anomaly), wHile Homozygous muta2ons cause prenatal death with skeletal defects and abnormal sterol metabolism (Greenberg dysplasia). ▪GREENBERG DYSPLASIA: THis severe condi2on is cHaracterized by abnormal bone forma2on and is fatal before birth. ResearcH suggest that this condi2on is caused by the loss of the sterol reductase func2on of the lamin B receptor. Some LBR gene muta2ons that cause Greenberg dysplasia cHange single amino acids in the sterol reductase domain of the lamin B receptor, wHicH leads to the loss of sterol reductase ac2vity. Other muta2ons lead to an abnormally sHort protein that is likely nonfunc2onal. Loss of the sterol reductase func2on of the lamin B receptor disrupts the normal synthesis of cHolesterol within cells. Absence of this func2on may also allow poten2ally toxic byproducts of cHolesterol synthesis to build up in the body's 2ssues. ResearcHers suspect that low cHolesterol levels or an accumula2on of other substances disrupt the growth and the development of many parts of the body. It is not known, However, How a disturbance of cHolesterol synthesis leads to the specific features of Greenberg dysplasia. Frequency: it is a very rare condi2on. Approximately ten cases Have been reported in the scien2fic literature. K ‒Embryos dead because of a disorder connected to the LBR gene Pa#ent associa#on(England):H^p://urddad-founda2on.org.uk/ ▪PELGER-HUËT: Muta2ons in the LBR gene can also cause Pelger-Huët anomaly, a condi2on that affects the sHape of the nucleus and the structure of the cHroma2n in certain cells but causes no outward signs or symptoms. THe nuclei of blood cells called granulocytes normally Have mul2ple segments (or lobes). In contrast, the nuclei of granulocytes in people with Pelger-Huët anomaly Have fewer segments than normal (they are Hypolobulated). In addi2on, the cHroma2n in affected cells appears coarser than usual wHen viewed under a microscope. Muta2ons that cause Pelger-Huët anomaly usually lead to an abnormally sHort lamin B receptor and reduce the amount of func2onal protein. It is thougHt that impairment of the receptor's DNA-binding domain leads to this condi2on. THe fact that the Healthy mother of the fetus sHowed Hypolobulated nuclei in 60% of Her granulocytes confirms that classic Pelger-Huët anomaly represents the Heterozygous state of 3beta-Hydroxysterol delta(14)-reductase deficiency. Incidence and therapies: THis condi2on does not affect the life of the person, so it’s useful a therapy. Moreover we can not make an es2mate of the frequency K ‒In the picture you can see the granulocytes affected by the the Pelger-Huet syndrome. THe immune system destroys these abnormal cells. Pa#ent associa#ons(Enlgand) H^p://urddad-founda2on.org.uk/ DISPLASIA DI GREENBERG Nome Gene: LBR, Lamin B Receptor Localizzazione cromosoma 1, 1q42.12, braccio lungo q, regione 42.12. ! Nome proteina: Lamin-B receptor. Accesso Uniprot: Q14739. Lunghezza: 615 amminoacidi Peso molecolare: 70703 Da Localizzazione subcellulare: Membrana interna dell’involucro nucleare Struttura 3D: da Proteopedia 2DIG Descrizione e Funzione: LBR (Lamin B Receptor) è un gene che fornisce istruzioni per la sintesi di una proteina chiamata “Lamin B receptor”. Le diverse regioni di questa proteina hanno funzioni distinte. Una porzione della proteina è coinvolta nella produzione del colesterolo (si parla di funzione sterolo-riduttasi); il colesterolo, infatti, oltre ad essere introdotto con la dieta, è prodotto dall’uomo e durante la sua sintesi questa regione della LBR permette di convertire una molecola chiamata lanosterolo in colesterolo. La produzione di colesterolo è essenziale per il normale funzionamento dell’organismo: infatti, prima della nascita il colesterolo interagisce con proteine che controllano lo sviluppo del cervello, dei genitali, degli arti; è inoltre un importante costituente delle membrane cellulari, della mielina (la struttura isolante delle cellule nervose) e serve per la produzione dei sali biliari, importanti per la digestione. Inoltre,il colesterolo è la molecola da cui derivano tutti gli ormoni steroidei. Un’altra regione della proteina LBR si lega alla cromatina, il complesso di DNA e proteine che costituisce i cromosomi. La proteina si trova nella membrana interna dell’involucro nucleare e, legando la lamina B media la corretta interazione tra eterocromatina e l’involucro nucleare,. giocando un importante ruolo in molte attività cellulare, come la duplicazione del DNA, il controllo dell’ attività dei geni e la morte cellulare programmata (apoptosi). La proteina è importante, inoltre, nella riformazione dell’involucro nucleareal termine della divisione cellulare. (https://www.genecards.org/cgi-bin/carddisp.pl?gene=LBR#summaries https://ghr.nlm.nih.gov/gene/LBR) Localizzazione cellulare Il gene è espresso principalmente nel sistema nervoso, nel fegato e nel sangue, mentre in modo minore nei polmoni, nell’intestino e nei muscoli. A livello cellulare, la proteina è localizzata principalmente nella membrana interna dell’involucro nucleare , e in modo minore anche nel reticolo endoplasmatico e nel citosol.. Mutazioni e Patologie: Le mutazioni in eterozigosi del LBR (‘anomalia di Pelger,) si manifestano con ‘iposegmentazione dei nuclei di neutrofili e eosinofili (che sono bilobati, invece di avere la solita struttura trilobata), mentre le mutazioni in omozigosi (sindrome di Greenberg) causano la morte prenatale per gravi deficienze dello sviluppo scheletrico e un’anormale metabolismo degli steroli. calcificazioni anomale nei tessuti molli, arti anteriori e posteriori più corti. , oltre alla anomala morfologia dei leucociti. "DISPLASIA DI GREENBERG: Mutazione: Autosomica recessiva (la patologia si manifesta solo quando entrambi gli alleli sono mutati). Diverse mutazioni del gene LBR sono state associate a questa malattia, che porta ad una formazione anormale delle ossa e alla morte prematura del feto. Ricerche hanno indicato che la malattia è causata dalla mancanza della funzione della sterolo reduttasi della proteina LBR. La perdita della funzione della sterolo-reduttasi interrompe la normale sintesi del colesterolo nella cellula. L’assenza di questa funzione può portare all’accumulo di sostanze tossiche nella cellula e causa effetti come idrope fetali (accumulo di liquidi nei tessuti del feto), nanismo grave con arti corti, anomalie del viso, ipoplasia (ridotto sviluppo) polmonare, polidattilia (presenza di dita sovrannumerarie) e igroma cistico (dilatazione degli spazi linfatici nel tessuto sottocutaneo del collo). Non è noto, tuttavia, il meccanismo mediante cui un disturbo nella sintesi del colesterolo possa portare alla displasia di Greenberg. (https://www.malacards.org/card/greenberg_dysplasia) Incidenza e terapia: É una malattia molto rara. Approssimativamente sono stati riportati dalla comunità scientifica solo 10 casi. Dato che i soggetti affetti decedono in età fetale, non si è in grado di creare nessuna terapia efficace per curare i sintomi della patologia. Embrioni morti a causa di una disfunzionalità correlata al gene LBR -Associazioni pazienti(Italia): http://www.fedra.org/ "ANOMALIA DI PELGER-HUËT: Mutazione: Autosomica (il gene si trova su un cromosoma non sessuale) dominante ( cioè si esprime anche se è presente in singola copia). Le mutazioni del gene LBR possono causare anche l’anomalia di Pelger-Huet, una condizione che riguarda il nucleo e la struttura della cromatina in alcune cellule, ma non porta a sintomi o segni esterni gravi, solo una bassa statura. I nuclei delle cellule del sangue, chiamati granulociti, hanno solitamente diversi segmenti. Al contrario i nuclei dei granulociti nelle persone con Pelger-Huet hanno meno segmenti del normale. In pratica, al microscopio, la cromatina nelle cellule affette appare più ruvida del normale. (https://www.malacards.org/card/pelger_huet_anomaly_with_mild_skeletal_anomalies) Incidenza e terapie Interessando le singole cellule è impossibile fare una stima. Non avendo ripercussioni sulla vita della persona non servono e non esistono cure. ! Granulociti di pazienti affetti dalla sindrome di Pelger-Huet. Quando il sistema immunitario li trova cerca di distruggerli, perché presentano un’anomalia. -Associazione pazienti(Italia): http://www.soditalia.it/ "SINDROME DI REYNOLDS: Le specifiche anomalie fibroblastiche (i fibroblasti sono le cellule tipiche e più numerose del tessuto connettivo, in grado di produrre le componenti della matrice extracellulare) osservate suggeriscono che questa particolare
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