GM27393

GM27393 Fibroblast

Description:

CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 1; CADASIL1
NOTCH, DROSOPHILA, HOMOLOG OF, 3; NOTCH3
HYPERHOMOCYSTEINEMIA
5,10-@METHYLENETETRAHYDROFOLATE REDUCTASE; MTHFR

Affected:

Yes

Sex:

Female

Age:

44 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases

Cell Type

Fibroblast

Tissue Type

Skin

Transformant

Untransformed

Race

White

Ethnicity

Not Hispanic/Latino

Ethnicity

Irish, English, German

Country of Origin

USA

Family Member

Family History

Relation to Proband

sister

Confirmation

Molecular characterization before cell line submission to CCR

Species

Homo sapiens

Common Name

Human

Remarks

Clinically affected; onset of symptoms at 35 years of age; diagnosed by a neurologist at 35 years; recurrent miscarriages; required anticoagulation and antiplatelet measures to achieve successful pregnancies; experienced postpartum focal neurological symptoms such as left visual field alteration with wavy lines, left hand and forearm numbness and tingling, and left face tingling - facial paresthesias without any definite motor weakness; generalized dull headache; borderline antiphospholipid antibodies – borderline elevation in anticardiolipin IgG (16, normal is <11) and antiphosphatidylinositol IgG (15) antibodies; hypotension; hypothyroid; history of Hashimoto’s thyroiditis; hyperhomocysteinemia; cardiovascular check during physical exam revealed that heart sounds are regular with a 2/6 systolic murmur; cranial and spinal MRIs demonstrated numerous intracranial T2 hyperintense lesions - possible CNS demyelination or microvascular disease; MRI also revealed minor mucosal thickening in the right maxillary and ethmoid sinus; brain MRA (magnetic resonance angiography) of the carotid arteries showed normal carotid bifurcations and patent vertebral arteries, left more dominant than right; normal ANA (anti-nuclear antibody test for lupus); on neurological exam, deep tendon reflexes were normal but exaggerated on the left, and a left Babinski sign was noted reflecting focal CNS dysfunction; sequencing of the Notch3 gene demonstrated a gain of a cysteine residue within one of the EGF-like repeats of the Notch3 receptor: c.511C>T (p.Arg141Cys) of the NOTCH3 ref seq (NM_000435.3), this autosomal dominant CADASIL-associated mutation of the Notch3 gene is associated with recurrent strokes; subject also has two mutations in the MTHFR gene: c.677C>T and c.1298A>C which confirms MTHFR syndrome; medications/treatments: Synthroid, Lovenox, previously on Levoxyl and aspirin, multivitamins; family history: mother and maternal uncle (neither in repository) were initially diagnosed with multiple sclerosis, but mother was later tested and found to be positive for CADASIL; mother also had lung cancer with brain metastasis, had mild dementia, decreasing mobility, and progressive weakness and died from complications; sister has Hashimoto’s Syndrome with hypothyroidism; LCL from patient is GM27171.

Characterizations

PDL at Freeze

4.68

Passage Frozen

IDENTIFICATION OF SPECIES OF ORIGIN

Species of Origin Confirmed by LINE assay

Gene

NOTCH3

Chromosomal Location

19p13.12

Allelic Variant 1

p.Arg141Cys; CADASIL

Identified Mutation

ARG141CYS; Autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a progressive disorder of the small arterial vessels of the brain manifest by migraine, strokes, and white matter lesions, with resultant cognitive impairment in some patients.

Gene

MTHFR

Chromosomal Location

1p36.3

Allelic Variant 1

607093.0003; MTHFR THERMOLABILE POLYMORPHISM

Identified Mutation

677C>T; Frosst et al. [Nature Genet. 10: 111-113 (1995)] identified a C-to-T substitution at nucleotide 677 that converted an alanine to a valine residue. The alteration created a HinfI site that was used to screen 114 unselected French-Canadian chromosomes; the allele frequency of the substitution was 0.38. The mutation in the heterozygous or homozygous state correlated with reduced enzyme activity and increased thermolability in lymphocyte extracts; in vitro expression of the mutagenized cDNA containing the mutation confirmed its effect on thermolability of MTHFR. Individuals homozygous for the mutation had significantly elevated plasma homocysteine levels. Thus, the 677C-T mutation may represent an important genetic risk factor in vascular disease.

Gene

MTHFR

Chromosomal Location

1p36.3

Allelic Variant 2

607093.0004; MTHFR THERMOLABILE POLYMORPHISM

Identified Mutation

1298A>C; Van der Put et al. (1998) identified another polymorphism of the MTHFR gene: a 1298A-C mutation that changed a glutamate into an alanine residue. The mutation destroyed an MboII recognition site and had an allele frequency of 0.33. The 1298A-C mutation resulted in decreased MTHFR activity, which was more pronounced in the homozygous than heterozygous state. Neither the homozygous nor the heterozygous state was associated with higher plasma homocysteine (Hcy) nor a lower plasma folate concentration--phenomena that are evident with homozygosity for the 677C-T mutation (236250.0003). However, combined heterozygosity at the 2 polymorphic sites was associated with reduced MTHFR-specific activity, higher Hcy, and decreased plasma folate levels. Thus, combined heterozygosity for both MTHFR mutations resulted in features similar to those observed in homozygotes for the 677C-T mutation. This combined heterozygosity was observed in 28% of the neural tube defect (NTD) patients compared with 20% among controls, resulting in an odds ratio of 2.04. The data suggested that combined heterozygosity for the 2 common mutations accounts for a proportion of folate-related NTDs, which is not explained by homozygosity for the 677C-T mutation.