GM25951

GM25951 LCL from B-Lymphocyte

Description:

MYOPATHY, CENTRONUCLEAR, 1; CNM1
TITIN; TTN
GAP JUNCTION PROTEIN, BETA-2; GJB2 (CONNEXIN 26; CX26)

Affected:

No

Sex:

Female

Age:

46 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases
Muscular Dystrophies
CMD Specific

Biopsy Source

Peripheral vein

Cell Type

B-Lymphocyte

Tissue Type

Blood

Transformant

Epstein-Barr Virus

Sample Source

LCL from B-Lymphocyte

Race

White

Ethnicity

Not Hispanic/Latino

Ethnicity

Irish/English/Polish

Country of Origin

USA

Family Member

Family History

Relation to Proband

mother

Confirmation

Molecular characterization before cell line submission to CCR

Species

Homo sapiens

Common Name

Human

Remarks

Affected carrier; history of ventricular ectopy; low normal ejection fraction (~52%); mild dilated cardiomyopathy; Hashimoto's thyroiditis at age 30; migraines with a visual aura; premature ovarian failure at age 37 years; low testosterone level; positive for antinuclear antibodies; after birth of son, began to experience muscle and joint pain; difficulty with prolonged standing, weakness in the lower extremities; normal CK (69); exam at age 44 revealed: neck flexion and proximal lower extremity weakness, echocardiogram :borderline normal left ventricular function, global LV hypokinesis, elevated right atrial pressure, trace tricuspid regurgitation, minimally thickened mitral valve, equivocal prolapse of the posterior mitral leaflet; doppler and color flow: trace mitral and trace tricuspid regurgitation; EKG: normal sinus rhythm with intermittent varying lengths of wide QRS rhythm episodes strongly suggestive of ventricular origin due to observed fusion beats, captured beats, and AV disassociation; MRI:consistent with a subclinical myopathy with abnormal ventricular volumes and borderline contractility; genetic testing revealed that the donor is heterozygous for a mutation in intron 191 of the TTN gene: c.37112-1 G>A, IVS191-1 G>A; donor subject is also heterozygous for a benign variant M34T (101T>C) in exon 2 of the GJB2 gene; medications: Lisinopril, Testosterone, Estradiol, Synthroid, Trazadone, Prometrium, and Plaquenil; son with centronuclear myopathy and connexin 26 hearing loss is GM23417-lymphoblast/GM25936-fibroblast; father of affected son is GM25948 (lymphoblast) and maternal grandmother of affected son is GM25993 (lymphoblast); family is referenced in Neurology (2013) 81:1205-14, PMID:23975875-affected son is subject 314-1.

Characterizations

IDENTIFICATION OF SPECIES OF ORIGIN

Species of Origin Confirmed by LINE assay

Gene

TTN

Chromosomal Location

2q31.2

Allelic Variant 1

; CENTRONUCLEAR MYOPATHY 1

Identified Mutation

37112-1G>A (IVS191-1G>A); Titin, or connectin, is a giant muscle protein expressed in the cardiac and skeletal muscles that spans half of the sarcomere from Z line to M line. Titin plays a key role in muscle assembly, force transmission at the Z line, and maintenance of resting tension in the I band region (Itoh-Satoh et al., 2002).

Gene

GJB2

Chromosomal Location

13q11-q12

Allelic Variant 1

121011.0001; GAP JUNCTION PROTEIN, BETA-2; GJB2

Identified Mutation

MET34THR; This variant, formerly titled DEAFNESS, AUTOSOMAL RECESSIVE 1A, has been reclassified based on the findings of Shearer et al. (2014). Based on allele frequency in 8,595 controls from 12 populations (maximum minor allele frequency = 0.0200), Shearer et al. (2014) recategorized the M34T variant in the GJB2 gene as benign. In a family in which both palmoplantar keratoderma and deafness (148350) were segregating as probably independent autosomal dominant traits (Verbov, 1987), Kelsell et al. (1997) identified a heterozygous T-to-C substitution in exon 1 of the GJB2 gene, resulting in a met34-to-thr (M34T) substitution. The M34T mutation appeared to segregate with profound deafness, but not with the skin disorder, suggesting to Kelsell et al. (1997) that the mutation acted in a dominant manner. However, Kelley et al. (1998) and Scott et al. (1998) observed normal hearing in M34T heterozygotes, suggesting that the variant does not function as a dominant GJB2 allele in vivo. Moreover, Kelley et al. (1998) identified the M34T allele in 3 of 192 control chromosomes, suggesting that it may be a polymorphism. By in vitro functional studies, White et al. (1998) observed a dominant-negative effect of the M34T mutant polypeptide on the intercellular coupling activity of the wildtype GJB2 polypeptide expressed in Xenopus oocytes. Griffith et al. (2000) presented evidence that M34T is a hypomorphic allele that is insufficient in itself to cause hearing loss, but may cause hearing loss when combined with another pathogenic GJB2 allele. They reported a family with severe autosomal recessive deafness (DFNB1A; 220290) associated with a homozygous mutation in the GJB2 gene (167delT; 121011.0010). One individual who was heterozygous for M34T had normal hearing, and another who was compound heterozygous for M34T and 167delT had only mild high frequency hearing loss. Houseman et al. (2001) found the prevalence of the M34T allele in a cohort of white sib pairs and sporadic cases with nonsyndromic sensorineural hearing loss from the United Kingdom and Ireland to be 3.179% of chromosomes screened. They found the homozygous M34T/M34T genotype cosegregating with mid to high frequency deafness. In a control population of 630 individuals, they identified 25 M34T heterozygotes but no M34T homozygotes. Eighty-eight percent of the M34T alleles were in cis with a 10-bp deletion in the 5-prime noncoding sequence. This deletion was homozygous in the M34T homozygotes. Houseman et al. (2001) concluded that M34T acts as a recessive allele. Kelsell et al. (2000) investigated the possible reason for normal hearing in M34T carriers from distinct ethnic populations. They stated that no M34T homozygotes had been reported among individuals with normal hearing. They extended their analysis of a small family in which palmoplantar keratoderma and various forms of deafness were segregating. In addition to the M34T sequence variant in GJB2, 2 other sequence variants were identified: D66H, also in GJB2 (121011.0012), and R32W in GJB3 (603324). As D66H segregated with the skin disease, Kelsell et al. (2000) thought it likely to underlie the palmoplantar keratoderma. The other 2 gap junction variants identified may contribute to the type of hearing impairment and the variable severity of the skin disease in the family. D'Andrea et al. (2002) showed that CX26 proteins carrying the M34T mutation were expressed at the cell surface and showed wildtype membrane distribution following transient transfection in HeLa cells, but they did not support dye transfer. The M34T mutant also acted as a dominant inhibitor of wildtype CX26 channel activity when the 2 proteins were coexpressed to mimic the heterozygous state. In contrast, Oshima et al. (2003) found that the M34T mutation supported dye transfer in HeLa cells at levels comparable to wildtype CX26, but a CX26 protein in which the authors introduced a met34-to-ala (M34A) mutation did not. In 11 French families with nonsyndromic sensorineural hearing loss (7 familial forms and 4 sporadic cases) in which the M34T variant had been identified, Feldmann et al. (2004) found that the mutation did not segregate with deafness in 6 of the 7 families. Of the family members with normal audiograms, 8 were heterozygous for M34T and 5 were compound heterozygous for M34T and another GJB2 mutation. A screening of 116 controls demonstrated an M34T allele frequency of 1.72%, which was not significantly different from the 2.12% frequency in the deaf population cited by Feldmann et al. (2004). Feldmann et al. (2004) suggested that the M34T variant is not clinically significant in humans and is a frequent polymorphism in France. In a study of 610 hearing-impaired individuals and 294 controls, Tang et al. (2006) found no significant difference in the M34T allele frequency between cases and controls, suggesting that the M34T variant is a polymorphism. Pollak et al. (2007) studied 233 Polish patients with hearing impairment and the GJB2 35delG mutation (121011.0005) on 1 allele. Analysis of 17 patients with the M34T/35delG and 12 patients with the V37I (121011.0023)/35delG genotypes, patients with other GJB2 mutations, and controls found that the M34T and V37I were significantly overrepresented among patients with hearing impairment, consistent with both variants being pathogenic. However, both mutations showed decreased penetrance of about 10% compared to mutations of undisputed pathogenicity. Also, patients with M34T/35delG and V37I/35delG had significantly later onset of hearing impairment compared to those with other genotypes. Pollak et al. (2007) suggested that the M34T and V37I mutations cause mild hearing impairment characterized by relatively late onset and progression.