GM21938

GM21938 Fibroblast from Skin, Unspecified

Description:

MARFAN SYNDROME; MFS
FIBRILLIN 1; FBN1

Affected:

Yes

Sex:

Female

Age:

36 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases

Biopsy Source

Unspecified

Cell Type

Fibroblast

Tissue Type

Skin

Transformant

Untransformed

Sample Source

Fibroblast from Skin, Unspecified

Race

White

Ethnicity

DUTCH

Relation to Proband

proband

Confirmation

Molecular characterization before cell line submission to CCR

Species

Homo sapiens

Common Name

Human

Remarks

Clinically affected; mildly dilated aortic root with diameters of 22mm at the annulus, 40mm at 1cm above the annulus, and 41mm maximum dilation; mitral valve prolapse; height 184cm; arm span of 186.7cm; thumb and wrist signs were negative; long narrow face; slightly high palate; minor asymmetry of the anterior chest wall; no scoliosis, joint hyperextensibility, sternal deformity, or contractures; no lens dislocation; shoe size 12 1/2; donor subject has a G>A change at nucleotide 3379 in exon 27 of the FBN1 gene (3379G>A) resulting in the substitution of serine for glycine at codon 1127 [Gly1127Ser (G1127S)]

Characterizations

PDL at Freeze

5.05

Passage Frozen

IDENTIFICATION OF SPECIES OF ORIGIN

Species of Origin confirmed by LINE assay

Gene

FBN1

Chromosomal Location

15q21.1

Allelic Variant 1

134797.0021; MARFAN SYNDROME, MILD

Identified Mutation

GLY1127SER; Francke et al. (1995) identified disease of the ascending aorta, ranging from mild aortic root enlargement to aneurysm and/or dissection, in 10 individuals of a kindred, none of whom had classic Marfan syndrome. Single-strand conformation analysis of the entire FBN1 cDNA of an affected family member demonstrated a G-to-A transition at nucleotide 3379, predicting a gly1127-to-ser substitution. The glycine in this position is highly conserved in EGF-like domains of FBN1 and other proteins. The mutation was present in 9 of 10 affected family members and in 1 young unaffected member, but was not found in other unaffected members in 168 chromosomes from normal controls, and in 188 chromosomes from other individuals with Marfan syndrome or related phenotypes. FBN1 intragenic marker haplotypes ruled out the possibility that the other allele played a significant role in modulating the phenotype in this family. Pulse-chase studies revealed normal fibrillin synthesis but reduced fibrillin deposition into the extracellular matrix in cultured fibroblasts from a gly1127-to-ser carrier. Francke et al. (1995) suggested that mutations such as this may disrupt EGF-like domain folding less dramatically than do substitutions of cysteine or other amino acids important for calcium-binding that cause classic Marfan syndrome. The proband in the family reported by Francke et al. (1995) was a 72-year-old woman, 174.5 cm tall, who was referred because of aortic root aneurysm, aortic regurgitation, and mitral valve prolapse. A brother had been discovered to have a type A aortic dissection with normal aortic valve and normal sinus of Valsalva at the age of 65 and successful surgical repair was performed. The findings in this family were consistent with the emerging recognition that FBN1 alterations produce a spectrum of connective tissue disorders that extend beyond the classic Marfan phenotype and for which the term fibrillinopathy has been proposed.

Phenotypic Data

Remarks

Publications

Zhang RM, Tiedemann K, Muthu ML, Dinesh NEH, Komarova S, Ramkhelawon B, Reinhardt DP, Fibrillin-1-regulated miR-122 has a critical role in thoracic aortic aneurysm formation Cellular and molecular life sciences : CMLS79:314 2022

PubMed ID: 35606547

Francke U, Berg MA, Tynan K, Brenn T, Liu W, Aoyama T, Gasner C, Miller DC, Furthmayr H, A Gly1127Ser mutation in an EGF-like domain of the fibrillin-1 gene is a risk factor for ascending aortic aneurysm and dissection American journal of human genetics56:1287-96 1995

PubMed ID: 7762551