GM25344

GM25344 Fibroblast from Skin, Skin

Description:

CONGENITAL DISORDER OF DEGLYCOSYLATION; CDDG
N-GLYCANASE 1; NGLY1
MALIGNANT HYPERTHERMIA SUSCEPTIBILITY 5; MHS5
CALCIUM CHANNEL, VOLTAGE-DEPENDENT, L TYPE, ALPHA-1S SUBUNIT; CACNA1S

Affected:

Yes

Sex:

Male

Age:

10 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases
PIGI Consented Sample

Biopsy Source

Skin

Cell Type

Fibroblast

Tissue Type

Skin

Transformant

Untransformed

Sample Source

Fibroblast from Skin, Skin

Race

White

Ethnicity

Not Hispanic/Latino

Country of Origin

USA

Family Member

Family History

Relation to Proband

proband

Confirmation

Molecular characterization before cell line submission to CCR

ISCN

46,XY[25].arr(1-22)x1,(X,Y)x1

Species

Homo sapiens

Common Name

Human

Remarks

Clinically affected; onset of symptoms at 12 months old; diagnosed at 10 years of age; ataxia; cerebral palsy; hypotonia; hand tremors; developmental delay; myopathic facial expression; whole exome sequence analysis reveals the subject is compound heterozygous for a p.Q208X variant (p.Gln208Stop, c.622 C>T) in exon 4 and a p.G310G variant (p.Gly310Gly, c.930 C>T) in exon 6 of the NGLY1 gene; subject also found to be heterozygous for a c.4060 A>T mutation (Thr1354Ser) in the CACNA1S gene – (malignant hyperthermia susceptibility; reported as ACMG incidental finding). Test was performed using genomic DNA, the whole exome sequence was mapped and analyzed in comparison with the published human genome build UCSC hg19 reference sequence; father (not in repository) is heterozygous for the Q208X mutation in the NGLY1 gene; mother (not in repository) is heterozygous for the G310G mutation in the NGLY1 gene and heterozygous for the Thr1354Ser mutation in the CACNA1S gene; sister with similar phenotype and the same genetic test results as this subject is GM25331 (lymphoblast) and GM25343 (fibroblast); same subject as GM25330 (lymphoblast) and GM27381 (stem cell).

Characterizations

PDL at Freeze

5.04

Passage Frozen

IDENTIFICATION OF SPECIES OF ORIGIN

Species of Origin Confirmed by LINE assay

Gene

NGLY1

Chromosomal Location

3p24.2

Allelic Variant 1

p.Q208X; CONGENITAL DISORDER OF DEGLYCOSYLATION; CDDG

Identified Mutation

GLN208TER

Gene

NGLY1

Chromosomal Location

3p24.2

Allelic Variant 1

p.G310G; CONGENITAL DISORDER OF DEGLYCOSYLATION; CDDG

Identified Mutation

GLY310GLY; The NGLY1 gene encodes N-glycanase (EC 3.5.1.52), a highly conserved enzyme that catalyzes deglycosylation of misfolded N-linked glycoproteins by cleaving the glycan chain before the proteins are degraded by the proteasome (Zhou et al., 2006). NGLY1 is a cytoplasmic component of the endoplasmic reticulum-associated degradation (ERAD) pathway that identifies and degrades misfolded glycoproteins (summary by Enns et al., 2014).

Gene

CACNA1S

Chromosomal Location

1q32.1

Allelic Variant 1

; MALIGNANT HYPERTHERMIA, SUSCEPTIBILITY TO, 5

Identified Mutation

THR1354SER; The major type of voltage-sensitive Ca(2+) channels in skeletal muscle is the slowly inactivating L-type that is sensitive to calcium channel blockers such as 1,4-dihydropyridines (DHP), phenylalkylamines, and benzothiazepines. These skeletal muscle Ca(2+) channels play a key role in excitation-contraction coupling, a process whereby electrical signals generated by action potentials at the muscle cell surface are transduced into intracellular release of calcium and ultimately muscle fiber contraction. The DHP-sensitive L-type Ca(2+) channel from skeletal muscle is an oligomeric protein composed of 2 high molecular weight polypeptide subunits (alpha-1 and alpha-2) and 3 smaller units (beta, gamma, and delta).