Molecular and clinical spectrum of type I plasminogen deficiency

TY - JOUR

T1 - Molecular and clinical spectrum of type I plasminogen deficiency

T2 - A series of 50 patients

AU - Tefs, Katrin

AU - Gueorguieva, Maria

AU - Klammt, Jürgen

AU - Allen, Carl M

AU - Aktas, Dilek

AU - Anlar, Fehim Y

AU - Aydogdu, Sultan D

AU - Brown, Deborah

AU - Ciftci, Ergin

AU - Contarini, Patricia

AU - Dempfle, Carl-Erik

AU - Dostalek, Miroslav

AU - Eisert, Susanne

AU - Gökbuget, Aslan

AU - Günhan, Omer

AU - Hidayat, Ahmed A

AU - Hügle, Boris

AU - Isikoglu, Mete

AU - Irkec, Murat

AU - Joss, Shelagh K

AU - Klebe, Sonja

AU - Kneppo, Carolin

AU - Kurtulus, Idil

AU - Mehta, Rakesh P

AU - Ornek, Kemal

AU - Schneppenheim, Reinhard

AU - Seregard, Stefan

AU - Sweeney, Elizabeth

AU - Turtschi, Stephanie

AU - Veres, Gabor

AU - Zeitler, Petra

AU - Ziegler, Maike

AU - Schuster, Volker

PY - 2006/11/1

Y1 - 2006/11/1

N2 - Severe type I plasminogen (PLG) deficiency has been causally linked to a rare chronic inflammatory disease of the mucous membranes that may be life threatening. Here we report clinical manifestations, PLG plasma levels, and molecular genetic status of the PLG gene of 50 patients. The most common clinical manifestations among these patients were ligneous conjunctivitis (80%) and ligneous gingivitis (34%), followed by less common manifestations such as ligneous vaginitis (8%), and involvement of the respiratory tract (16%), the ears (14%), or the gastrointestinal tract (2%). Four patients showed congenital occlusive hydrocephalus, 2 with Dandy-Walker malformation of cerebellum. Venous thrombosis was not observed. In all patients, plasma PLG levels were markedly reduced. In 38 patients, distinct mutations in the PLG gene were identified. The most common genetic alteration was a K19E mutation found in 34% of patients. Transient in vitro expression of PLG mutants R134K, delK212, R216H, P285T, P285A, T319_N320insN, and R776H in transfected COS-7 cells revealed significantly impaired secretion and increased degradation of PLG. These results demonstrate impaired secretion of mutant PLG proteins as a common molecular pathomechanism in type I PLG deficiency.

AB - Severe type I plasminogen (PLG) deficiency has been causally linked to a rare chronic inflammatory disease of the mucous membranes that may be life threatening. Here we report clinical manifestations, PLG plasma levels, and molecular genetic status of the PLG gene of 50 patients. The most common clinical manifestations among these patients were ligneous conjunctivitis (80%) and ligneous gingivitis (34%), followed by less common manifestations such as ligneous vaginitis (8%), and involvement of the respiratory tract (16%), the ears (14%), or the gastrointestinal tract (2%). Four patients showed congenital occlusive hydrocephalus, 2 with Dandy-Walker malformation of cerebellum. Venous thrombosis was not observed. In all patients, plasma PLG levels were markedly reduced. In 38 patients, distinct mutations in the PLG gene were identified. The most common genetic alteration was a K19E mutation found in 34% of patients. Transient in vitro expression of PLG mutants R134K, delK212, R216H, P285T, P285A, T319_N320insN, and R776H in transfected COS-7 cells revealed significantly impaired secretion and increased degradation of PLG. These results demonstrate impaired secretion of mutant PLG proteins as a common molecular pathomechanism in type I PLG deficiency.

KW - Animals

KW - Blood Coagulation Disorders

KW - Conjunctivitis

KW - Gene Expression Regulation

KW - Heterozygote Detection

KW - Humans

KW - Mice

KW - Mice, Knockout

KW - Plasminogen

KW - Protein Conformation

U2 - 10.1182/blood-2006-04-017350

DO - 10.1182/blood-2006-04-017350

M3 - SCORING: Journal article

C2 - 16849641

VL - 108

SP - 3021

EP - 3026

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 9

ER -