Alternative titles; symbols
HGNC Approved Gene Symbol: LDB3
Cytogenetic location: 10q23.2 Genomic coordinates (GRCh38) : 10:86,666,788-86,736,072 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q23.2 | Cardiomyopathy, dilated, 1C, with or without LVNC | 601493 | Autosomal dominant | 3 |
| Cardiomyopathy, hypertrophic, 24 | 601493 | Autosomal dominant | 3 | |
| Left ventricular noncompaction 3 | 601493 | Autosomal dominant | 3 | |
| Myopathy, myofibrillar, 4 | 609452 | Autosomal dominant | 3 |
The LDB3 gene encodes a PDZ-LIM domain-binding factor that plays an important role in maintaining the structural integrity of the striated muscle Z-disc in multiple species (summary by Lin et al., 2014).
By screening muscle cDNA libraries with a muscle EST sequence as probe, Faulkner et al. (1999) obtained cDNAs encoding mouse and human ZASP. The deduced 283-amino acid human ZASP protein has an 85-residue N-terminal PDZ domain and shares significant similarity with the 734-amino acid protein encoded by the KIAA0613 cDNA isolated by Ishikawa et al. (1998). Database, PCR, and genomic DNA analyses indicated the presence of alternatively spliced isoforms of ZASP that encode proteins of 470, 617, and 727 (KIAA0613) amino acids. Northern blot analysis detected a major 1.9-kb ZASP transcript that was most abundant in skeletal muscle and heart but absent in other tissues tested. Additional transcripts of 4.0 and 5.4 kb were detected when using a 5-prime rather than a 3-prime probe. RT-PCR analysis detected wide expression of KIAA0613, with weak or undetectable expression in liver, pancreas, and spleen (Ishikawa et al., 1998). Western blot analysis showed expression of 32- and 78-kD proteins in heart and muscle. Immunofluorescence microscopy demonstrated that ZASP was expressed in pseudopodia and in the cytoplasm around the nucleus, and that it colocalized with actin in the I-band. Immunoelectron microscopy localized ZASP within the Z-band.
Zhou et al. (1999) identified splice variants of the mouse homolog of ZASP, which they termed termed Cypher1 (723 residues) and Cypher2 (288 residues). The longer variant has a LIM domain that interacts with protein kinase C (see 176982).
Huang et al. (2003) identified 6 isoforms of mouse Cypher, including the 2 isoforms identified by Zhou et al. (1999). The 6 isoforms could be divided into skeletal- or cardiac-specific classes based on the inclusion of skeletal- or cardiac-specific domains following the common N-terminal PDZ domain. Each class contains a short isoform and 2 long isoforms. The long isoforms in each class differ from one another in the sequence following the cardiac- or skeletal-specific domain, but both have 3 C-terminal LIM domains. Huang et al. (2003) found that expression of the Cypher isoforms was developmentally regulated. One long isoform predominated in mouse heart throughout development, but in skeletal muscle, the predominant long isoform switched during maturation of embryonic to neonatal skeletal muscle. The skeletal- and cardiac-specific short isoforms were only expressed postnatally.
Human skeletal muscle has 3 isoforms of LDB3, which are generated by alternative splicing of exons 9 and 10. The prenatal long isoform contains exon 10 (ZASP-L), and the postnatal long isoform lacks exon 10 (ZASP-Ldelex10). Both long isoforms include an N-terminal PDZ domain, an internal ZASP-like motif encoded by exon 6, and 3 C-terminal LIM domains. The short isoform (ZASP-S) has a stop codon in exon 9 and lacks the LIM domains. The PDZ domains interact with alpha-actinin-2 (ACTN2; 102573), and the LIM domains bind to protein kinase C (see, e.g., PRKCA; 176960) (summary by Lin et al., 2014).
Vatta et al. (2003) determined that the LDB3 gene contains 16 exons and spans approximately 70 kb.
Huang et al. (2003) determined that the mouse Cypher gene contains 17 exons. The cardiac-specific region is encoded by exon 4, and the skeletal muscle-specific region is encoded by exons 5 through 7. Exon 7 is skipped in one of the skeletal muscle splice variants.
By radiation hybrid analysis, Ishikawa et al. (1998) mapped the KIAA0613 gene, or ZASP, to chromosome 10. Using PCR and radiation hybrid analysis, Faulkner et al. (1999) localized the ZASP gene to 10q22.2-q23.3.
PDZ domain-containing proteins interact with each other in cytoskeletal assembly or with other proteins involved in targeting and clustering of membrane proteins. By yeast 2-hybrid analysis, Faulkner et al. (1999) determined that the PDZ domain of ZASP interacts with the C terminus of alpha-actinin-2 (ACTN2; 102573).
By yeast 2-hybrid analysis, Frey and Olson (2002) showed that ZASP interacted strongly with MYOZ1 (605603), MYOZ2 (605602), and MYOZ3 (610735). Coimmunoprecipitation studies in COS-7 cells showed that both the longest and shortest ZASP splice variants bind all 3 members of the myozenin family, suggesting that the interaction is not isoform specific.
By yeast 2-hybrid analysis and coimmunoprecipitation studies, Lin et al. (2014) found that the internal striated muscle ZASP-like motif (sZM) of the LDB3 protein interacted with the C terminus of ACTA1 (102610), specifically with residues 287-325. Exon 6 of LDB3 alone was sufficient for interaction with ACTA1. The long ZASP isoform lacking exon 10 also interacted with ACTA1, indicating an additional actin-binding region encoded by the exon 8-11 junction that is not present in the other isoforms. These findings suggested that this postnatal isoform is important for skeletal muscle structural integrity. The sZM domain did not bind to ACTN2.
Myofibrillar Myopathy 4
In 11 of 54 unrelated patients with myofibrillar myopathy (MFM4; 609452), Selcen and Engel (2005) identified 3 different heterozygous missense mutations in the ZASP gene (A147T, 605906.0001; A165V, 605906.0002; and R268C, 605906.0003). The first 2 mutations occurred in exon 6, whereas R268C occurred in exon 9.
In affected members of a large multigenerational family with adult-onset distal myopathy originally reported by Markesbery et al. (1974), Griggs et al. (2007) identified a heterozygous missense mutation in the ZASP gene (A165V; 605906.0002). Haplotype analysis in this family and in 5 other families of European ancestry with this mutation showed a founder effect.
Lin et al. (2014) found that the LDB3 A147T and A165V mutant proteins interacted with globular and filamentous ACTA1, similar to wildtype. The mutations also did not affect LDB3 interaction with ACTA2. However, transfection of the mutant proteins, but not wildtype, resulted in disruption of filamentous actin (F-actin) stress fibers in muscle cells. Mouse skeletal muscle samples that had been electroporated with the mutant A165V protein showed a loss of the F-actin cross-linking proteins Actn2 and myotilin (MYOT; 604103) from the Z-discs as well as accumulation of mutant A165V in the sarcoplasm. These changes were not observed in mice expressing GFP-tagged wildtype LDB3. Lin et al. (2014) concluded that the long isoform lacking exon 10 has an essential role in the maintenance of skeletal muscle structure, and that the myopathy phenotype results from altered F-actin dynamics.
Dilated Cardiomyopathy 1C and Left Ventricular Noncompaction 3
Vatta et al. (2003) evaluated the role of Cypher/ZASP in the pathogenesis of dilated cardiomyopathy with or without noncompaction of the left ventricular myocardium (CMD1C; 601493). They screened 100 probands with left ventricular dysfunction and identified heterozygosity for 5 missense mutations in the LDB3 gene (605906.0004-605096.0008) in 6 probands (6%), 2 of whom had CMD alone and 4 of whom also had left ventricular noncompaction. None of the mutations were found in 200 ethnically matched controls. By in vitro studies, they showed cytoskeleton disarray in cells transfected with mutated Cypher/ZASP.
Arimura et al. (2004) searched for LDB3 mutations in 96 unrelated Japanese patients with dilated cardiomyopathy who were negative for mutation in 11 other cardiomyopathy-related genes. A heterozygous missense mutation (D626N; 605906.0009) was identified in a late-onset familial case. The authors demonstrated that the D626N mutation increased the affinity of the LIM domain for protein kinase C, suggesting a novel biochemical mechanism of the pathogenesis of dilated cardiomyopathy.
In 4 affected members of 2 unrelated Japanese families with left ventricular noncompaction (LVNC3; see 601493), Xing et al. (2006) identified heterozygosity for the D626N substitution.
In 2 large Bedouin Israeli families with CMD and LVNC, Levitas et al. (2016) detected the D117N variant in the LDB3 gene (605906.0007) but found that it did not segregate with disease. In addition, the prevalence of the variant in the general Bedouin population from the same region of southern Israel was much higher than the incidence of idiopathic CMD in that population. Levitas et al. (2016) concluded that, at least in the Bedouin population, D117N is not the causative mutation for these cardiac abnormalities, and suggested that it may not be causative in other patients as well.
Hypertrophic Cardiomyopathy 24
In 6 unrelated patients with hypertrophic cardiomyopathy (CMH24; see 601493), Theis et al. (2006) identified 5 different heterozygous missense mutations in the LDB3 gene (see, e.g., 605906.0005 and 605906.0010).
Huang et al. (2003) found that Cypher-null mice died within the first week of birth. Knockin of either a short or long skeletal muscle-specific isoform rescued the lethal phenotype, although the surviving mice exhibited muscle pathology.
Zhou et al. (2001) found that homozygous Cypher-null mice were either not viable or died by postnatal day 5 from respiratory insufficiency. The mice also showed limb weakness, inability to suckle, and right and left cardiac ventricular dilatation. Ultrastructural examination showed that active skeletal and cardiac muscle of the mutant mice displayed disorganized and fragmented Z lines, whereas noncontracting embryonic muscles had normal Z line structure. The findings were consistent with a myopathy, not a muscular dystrophy, suggesting that Cypher is required for striated muscle function and maintenance during the stress of contraction, but not for initial formation of the Z line. In vitro studies showed that individual domains within Cypher localize independently to the Z line. Targeted deletion studies showed that the Cypher PDZ domain binds to the last 3 amino acids of the ACTN2 C terminus. Zhou et al. (2001) concluded that Cypher acts as a linker-strut in muscle and suggested that mutations in the human ZASP gene could result in congenital myopathies with cardiac involvement.
Zheng et al. (2009) showed that cardiac-specific Cypher knockout (CKO) mice developed a severe form of dilated cardiomyopathy (DCM) with disrupted cardiomyocyte ultrastructure and decreased cardiac function, which eventually led to death before 23 weeks of age. A similar phenotype was observed in inducible cardiac-specific CKO mice in which Cypher was specifically ablated in adult myocardium. In both cardiac-specific CKO models, ERK (EPHB2; 600997) and Stat3 (102582) signaling pathways were augmented. Yeast 2-hybrid assay and Western blot analysis demonstrated specific binding of the Cypher PDZ domain to the C-terminal region of both calsarcin-1 (MYOZ2; 605602) and myotilin (TTID; 604103) within the Z line. Zheng et al. (2009) suggested that Cypher plays a pivotal role in maintaining adult cardiac structure and cardiac function through protein-protein interactions with other Z-line proteins, and specific signaling pathways participate in Cypher mutant-mediated dysfunction of the heart, and may in concert facilitate the progression to heart failure.
Cheng et al. (2011) found that targeted deletion of the Cypher short (CypherS) isoforms, which lack the 3 C-terminal LIM domains, had no effect on mouse survival, growth, or cardiac function. However, targeted deletion of the Cypher long (CypherL) isoforms, which contain the LIM domains, caused significant postnatal mortality, growth retardation, cardiomyopathy beginning at 9 months, and premature adult mortality. Young CypherL-knockout hearts showed increased susceptibility to biomechanical and beta-adrenergic stress. Prior to development of dilated cardiomyopathy, CypherL-knockout mice displayed cardiac muscle Z-line abnormalities and inotropic and lusitropic dysfunction accompanied by aberrant signaling via calcineurin (see 114105)-NFAT (see 600489) and PKC (see 176960) pathways.
In 7 unrelated patients with myofibrillar myopathy (MFM4; 609452), Selcen and Engel (2005) identified a heterozygous c.464G-A transition in exon 6 of the LDB3 gene, resulting in an ala147-to-thr (A147T) substitution in a conserved region immediately before the ZM motif needed for interaction with alpha-actinin (see, e.g., ACTN1, 102575). Five patients had a family history of the disorder; the A147T mutation was identified in affected family members of 1 proband. All patients had progressive proximal and/or distal weakness, 3 patients had cardiac involvement, and 2 had evidence of peripheral neuropathy. The mutation was not identified in 220 control alleles.
In 3 unrelated patients with myofibrillar myopathy (MFM4; 609452), Selcen and Engel (2005) identified a heterozygous c.519C-T transition in exon 6 of the LDB3 gene, resulting in an ala165-to-val (A165V) substitution within the ZM motif needed for interaction with alpha-actinin (see, e.g., ACTN1, 102575). Two patients had a family history of the disorder. All had progressive weakness that was more severe distally, 1 had cardiac involvement, and 2 had evidence of peripheral neuropathy. The mutation was not identified in 220 control alleles.
In affected members of a large multigenerational family with adult-onset distal myopathy originally reported by Markesbery et al. (1974), Griggs et al. (2007) identified a heterozygous A165V mutation in the ZASP gene. Haplotype analysis of this family and in 5 other families of European ancestry with this mutation showed a founder effect. Western blot analysis of patient skeletal muscle showed normal amount of ZASP protein isoforms similar to controls. Functional studies of the variant were not performed.
In a patient with myofibrillar myopathy (MFM4; 609452), Selcen and Engel (2005) identified a heterozygous c.827C-T transition in exon 9 of the LDB3 gene, resulting in an arg268-to-cys (R268C) substitution. Exon 9 is only present in the short muscle transcript of the gene. This patient had a late-onset at age 73 years and had no cardiac involvement, suggesting that the longer LDB3 isoforms may have partially compensated for the defect.
In 3 affected members of a family with 'pure' dilated cardiomyopathy (CMD1C; 601493) and an autosomal dominant inheritance pattern, Vatta et al. (2003) identified heterozygosity for a 1056C-G transversion in exon 10 of the LDB3 gene, resulting in an ile352-to-met (I352M) substitution. The proband and her affected brother and father also had left ventricular hypertrophy by electrocardiography. The mutation was not found in her unaffected sister or in 200 ethnically matched controls.
Dilated Cardiomyopathy 1C with Left Ventricular Noncompaction
In a 40-year-old man with dilated cardiomyopathy associated with severe left ventricular hypertrophy and a trabeculated left ventricle on echocardiogram (CMD1C; 601493), Vatta et al. (2003) identified heterozygosity for a 587C-T transition in exon 4 of the LDB3 gene, resulting in a ser196-to-leu (S196L) substitution. Four other family members were affected: the proband's 68-year-old mother; his 2 brothers, 1 of whom died with severe dilated cardiomyopathy at age 41 years; and the deceased brother's 7-year-old daughter, who presented with a mildly dilated left ventricle. The proband's mother and living brother both also had severe left ventricular hypertrophy. The mutation was not found in 200 ethnically matched controls.
Familial Hypertrophic Cardiomyopathy 24
In 2 unrelated women with hypertrophic cardiomyopathy (CMH24; see 601493), who were diagnosed at 63 and 73 years of age, Theis et al. (2006) identified heterozygosity for the S196L mutation in the LDB3 gene. The woman who was diagnosed at age 73 had a maximum left ventricular wall thickness (MLVWT) of 19 mm and exhibited a sigmoid septal shape; she was treated with myectomy, and marked myocyte hypertrophy, moderate endocardial fibrosis, and focal myocyte disarray were noted on histopathologic examination. The woman who was diagnosed at age 63 had an MLVWT of 13 mm, with an apical septal shape; she was treated pharmacologically. Neither patient had a family history of CMH or sudden cardiac death.
In a 15-month-old Latin American male with profound bradycardia, atrial ventricular block, and depressed ventricular function with mild left ventricular dilation (CMD1C; 601493), Vatta et al. (2003) identified heterozygosity for a 638C-T transition in exon 4 of the LDB3 gene, resulting in a thr213-to-ile (T213I) substitution. Thr213 is conserved in mouse and rat. Neither parent had the substitution.
This variant, formerly titled CARDIOMYOPATHY, DILATED, 1C, WITH LEFT VENTRICULAR NONCOMPACTION, has been reclassified based on the findings of Levitas et al. (2016).
In 2 unrelated sporadic cases of dilated cardiomyopathy with left ventricular noncompaction (CMD1C; 601493), Vatta et al. (2003) identified heterozygosity for a 349G-A transition in exon 6 of the LDB3 gene, resulting in an asp117-to-asn (D117N) mutation. One patient was a 44-year-old female, diagnosed at 41 years of age with DCM, heart failure, left bundle branch block, and dilated left ventricle with deep trabeculations. The other was a 33-year-old male, diagnosed with DCM at 30 years of age during a family echocardiographic screen after sudden death had occurred within the family. Echocardiographic and MRI screening identified both left and right ventricular trabeculations, with severe left ventricular hypertrophy, an intraventricular conduction delay, and ventricular bigeminy on electrocardiogram, as well as echocardiographic evidence of borderline systolic function and a dilated left ventricle. In the other family members, neither DCM nor isolated noncompaction of the left ventricular myocardium was identified.
Levitas et al. (2016) studied 2 large Bedouin Israeli families segregating autosomal dominant CMD and ventricular arrhythmias, with focal LVNC in some patients of the first family and apical trabeculations compatible with a mild variant of LVNC in some patients of the second family. Analysis of 100 cardiomyopathy-associated genes revealed only 1 putative mutation, the D117N variant in the LDB3 gene. However, the variant was present in only 6 of 16 genotyped patients, and was also detected in 5 healthy family members who were thoroughly evaluated. In addition, there was no apparent correlation between disease severity and the presence of D117N. Analysis of the prevalence of the variant in unrelated individuals from the general Bedouin population from the same region of southern Israel revealed it to be present in heterozygosity in 11 (5.2%) of 210 chromosomes, which was much higher than the incidence of idiopathic CMD in that population. The authors also noted that this variant has a prevalence of 0.65% and 1% in the 1000 Genomes Project and ClinSeq databases, respectively, and is present at 0.3% in European Americans and 1.2% in African Americans in the Exome Variant Server database. Levitas et al. (2016) concluded that, at least in the Bedouin population, D117N is not the causative mutation for these cardiac abnormalities, and suggested that it may not be causative in other patients as well.
In a 16-year-old Caucasian male with the diagnosis of dilated cardiomyopathy (CMD1C; 601493) by echocardiography and left ventricular hypertrophy on electrocardiography, Vatta et al. (2003) identified heterozygosity for a 407A-T transversion in exon 6 of the LDB3 gene, resulting in a lys136-to-met (K136M) substitution.
Dilated Cardiomyopathy 1C
In a Japanese family with dilated cardiomyopathy (CMD1C; 601493), Arimura et al. (2004) found heterozygosity for a G-to-A transition in exon 15 of the LDB3 gene, resulting in an asp626-to-asn (D626N) substitution at a conserved residue within the third LIM domain. All affected sibs had the same mutation, which was not found in 400 unrelated healthy controls; 1 sister, aged 65, had the mutation but did not have dilated cardiomyopathy. Clinical information suggested that cardiomyopathy was of late onset.
Left Ventricular Noncompaction 3
In 4 affected members of 2 unrelated Japanese families with left ventricular noncompaction (LVNC3; see 601493), Xing et al. (2006) identified heterozygosity for a 1876G-A transition in exon 15 of LDB3, resulting in the D626N substitution. The mutation was not found in 200 controls. In the first family, twin sisters presented with isolated LVNC shortly after birth; their father and paternal grandfather were reportedly diagnosed with LVNC and dilated cardiomyopathy, but DNA was not available for study. In the second family, the male proband was diagnosed with isolated LVNC and Wolff-Parkinson-White syndrome (WPW; 194200) on routine physical examination at 13 years of age; his asymptomatic mutation-positive mother was found to have LVNC on echocardiography. A maternal aunt died at 10 years of age of indistinct cardiac disease.
In a man who was diagnosed at 28 years of age with hypertrophic cardiomyopathy (CMH24; see 601493), Theis et al. (2006) identified heterozygosity for a pro615-to-leu (P615L) substitution in the LDB3 gene. The patient had a maximum left ventricular wall thickness of 27 mm and exhibited a sigmoid septal shape. He was treated with myectomy, and moderate myocyte hypertrophy with mild to moderate focal endocardial fibrosis was noted on histopathologic examination. There was no family history of CMH or sudden cardiac death.
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