GM23417

GM23417 LCL from B-Lymphocyte

Description:

MYOPATHY, CENTRONUCLEAR, 1; CNM1
MYOPATHY, PROXIMAL, WITH EARLY RESPIRATORY MUSCLE INVOLVEMENT; MPRM
TITIN; TTN
GAP JUNCTION PROTEIN, BETA-2; GJB2 (CONNEXIN 26; CX26)

Affected:

Yes

Sex:

Male

Age:

9 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases
Muscular Dystrophies
CMD Specific

Class

Congenital Muscle Diseases

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

POLISH/IRISH/ENGLISH

Country of Origin

USA

Family Member

Family History

Relation to Proband

proband

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

Clinically affected; Centronuclear myopathy and connexin 26 hearing loss; born full term via normal spontaneous delivery; birth weight 6lb 9 oz; apgar scores: 9 at 1 min and 9 at 5 min; failed initial newborn hearing screening but passed repeat test several weeks later; hyporeflexia and hypotonia onset at 2 months of age; head lag and developmental delay noted at 5 months due to severe weakness of neck muscles; weakness of arms, legs; scoliosis; physical exam at 11 years 6 months: subject noted to be ambulant but had difficulty lifting head or torso against gravity and fatigued easily, had decreased vital capacity, facial weakness, and absent deep tendon reflexes; developmental milestones achieved and maintained through age 11: sat at 9 months, held head up and turned in bed at 12 months, stood at 14 months, walked indoors at 16 months, and walked outdoors at 18 months; climbed stairs with a handrail at 24 months; ran (feet leaving ground) at 5 years; Muscle biopsy at age 14 months: revealed marked increase in the number of fibers with internal and central nuclei, fiber size variation, Type I fiber predominance, and increase in connective or endomysial tissue; electron micrograph of muscle biopsy revealed: disintegrated sarcomeres showing disrupted I- and A-band regions; indirect immunofluorescence analysis of the muscle biopsy indicated normal sarcomere labeling with the titin N-terminal and A-I junction antibodies (titin integrated into sarcomeres and structure intact up to A-I junction), but there was complete loss at the C-terminal of titin which contains a binding site for calpain 3 (CAPN3); immunostaining for CAPN3 indicated a loss of the CAPN3 binding region on the mutant titin proteins; reduced immunostaining for AldoA receptors indicated that the mutations lie in the titin N2-line region; whole exome sequencing was performed (UCSC hg19); subject is a compound heterozygote for the following mutations in the TTN gene; mutation 1 (paternal) in exon 168: p.Val10952Leu (GTT>CTT), c.32854G>C; mutation 2 (maternal) intron 191: c.37112-1G>A, IVS191-1 G>A; audiology evaluation at age 5: mild sensorineural hearing loss on the left side; repeat audiological evaluations every six months revealed progressive hearing loss, L>R; audiological exam at age 8 years: mild sensorineural hearing loss 250-1500 Hz rising within normal limits through 8000 Hz in right ear and a mild sloping to a moderately severe sensorineural hearing loss 250-2000 Hz rising to within normal limits through 8000 Hz in left ear, middle ear muscle reflexes absent to contralateral stimulation 500-2000 Hz, stimulating either ear, distortion-product otoacoustic emissions were consistent with a low to mid frequency hearing loss; word recognition excellent bilaterally; excellent speech perception at average conversation levels (50 dB); Connexin 26 GJB2 gene sequencing revealed subject is heterozygous for 342kb deletion (35delG) and heterozygous for an M34T change, which was reported to be sufficient to result in significant hearing loss when inherited in combination with 35delG in 2007 at the time of testing; subject uses Widex Inteo SD-9M post auricular hearing aids; subject uses breathing support at night or when ill; carrier mother has mild subclinical cardiac and skeletal myopathy, no other family history of centronuclear myopathy or connexin 26 hearing loss; subject fibroblast cell line is GM25936; carrier mother is GM25951 (lymphoblast), unaffected carrier father is GM25948 (lymphoblast), and maternal grandmother is GM25993 (lymphoblast); subject is 314-1 in Neurology (2013) 81:1205-14, PMID:23975875.

Characterizations

IDENTIFICATION OF SPECIES OF ORIGIN

Species of Origin Confirmed by LINE assay

IDENTIFICATION OF SPECIES OF ORIGIN

Species of Origin Confirmed by LINE assay

Gene

TTN

Chromosomal Location

2q31.2

Allelic Variant 1

VAL10952LEU; CENTRONUCLEAR MYOPATHY 1

Identified Mutation

32854 G>C; 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

TTN

Chromosomal Location

2q31.2

Allelic Variant 1

VAL10952LEU; CENTRONUCLEAR MYOPATHY 1

Identified Mutation

Gene

TTN

Chromosomal Location

2q31.2

Allelic Variant 2

; 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

TTN

Chromosomal Location

2q31.2

Allelic Variant 2

; CENTRONUCLEAR MYOPATHY 1

Identified Mutation

Phenotypic Data

Remarks

Publications

Ceyhan-Birsoy O, Agrawal PB, Hidalgo C, Schmitz-Abe K, DeChene ET, Swanson LC, Soemedi R, Vasli N, Iannaccone ST, Shieh PB, Shur N, Dennison JM, Lawlor MW, Laporte J, Markianos K, Fairbrother WG, Granzier H, Beggs AH, Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy Neurology81:1205-14 2013

PubMed ID: 23975875