HGNC Approved Gene Symbol: NEB
Cytogenetic location: 2q23.3 Genomic coordinates (GRCh38) : 2:151,485,339-151,734,476 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q23.3 | Arthrogryposis multiplex congenita 6 | 619334 | Autosomal recessive | 3 |
| Nemaline myopathy 2, autosomal recessive | 256030 | Autosomal recessive | 3 |
Nebulin is a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle. In most vertebrates, nebulin accounts for 3 to 4% of the total myofibrillar protein and its size varies from 600 to 800 kD in a manner that is tissue-, species-, and developmental stage-specific (Stedman et al., 1988). A variety of nebulin isoforms are thought to contribute to the molecular diversity of Z discs (Pelin et al., 1999).
Using polyclonal nebulin antisera to screen a cDNA expression library, Stedman et al. (1988) isolated 2 separate human fetal muscle cDNA clones. Both cDNAs detected a 25-kb skeletal muscle RNA transcript.
Zeviani et al. (1988) also isolated 2 nonoverlapping cDNAs encoding human nebulin.
Wang et al. (1996) isolated 2 partial cDNA sequences of fetal skeletal muscle nebulin, and Labeit and Kolmerer (1995) obtained the nearly identical sequence of a complete 20.8-kb cDNA encoding adult nebulin (the few changes may be due to sequencing errors or polymorphisms). The 6,669-residue (773 kD) predicted protein contains 185 copies of 35-amino acid modules that can be classified into 7 types. Labeit and Kolmerer (1995) suggested alternative splicing as the explanation for developmental or tissue-specific size variants of nebulin. They speculated that features at the C-terminal end of the protein, including an SH3 domain (which is also found in yeast actin-binding protein), may anchor nebulin to the Z disc of the sarcomere.
Donner et al. (2004) found that the NEB protein contains an N-terminal glutamic acid-rich domain followed by a tropomodulin-binding region; a central region containing simple repeats, super repeats of 7 simple repeats, and a desmin-binding region; and a C-terminal titin- and myopalladin-binding region, which anchors the protein in the Z disc. They also determined that the NEB gene encodes numerous splice variants.
Donner et al. (2004) determined that the nebulin gene contains 183 exons in a 249-kb genomic region. The translation initiation codon is in exon 3, and the stop codon and the 3-prime untranslated region are in exon 183. The central region of the gene harbors an approximately 8.2-kb region spanning 8 exons, which is duplicated twice (exons 82 to 89, exons 90 to 97, and exons 98 to 105). The duplicated segments are 99% identical. Introns 89, 97, and 105 contain LINE-2 repetitive elements. There are 4 regions with alternatively spliced exons: exons 63 to 66, 82 to 105, 143 and 144, and 166 to 177.
Stedman et al. (1988) localized 2 human nebulin cDNAs from fetal muscle to chromosome 2. By hybridization to DNA isolated from rodent-human cell hybrids, Zeviani et al. (1988) assigned the human nebulin gene to chromosome 2 and, by in situ hybridization, sublocalized it to region 2q31-q32.
By fluorescence in situ hybridization, Limongi et al. (1997) demonstrated that the NEB gene is located on 2q24.2, whereas the gene encoding the alpha-1 chain of type III collagen (120180) is located on 2q32.2. The FRA2 gene common fragile site lies between the 2 genes in the 2q31 band.
Pelin et al. (1997) used radiation hybrid mapping to reassign the nebulin gene close to the microsatellite marker D2S2236 on 2q22. They concluded that the nebulin gene resides within the candidate region for NEM2 (256030), a form of autosomal recessive nemaline myopathy.
Using 5 different series of recombinant inbred strains, Schurr et al. (1991) mapped the mouse nebulin gene to proximal chromosome 2.
In many tissues, actin monomers polymerize into actin (thin) filaments of precise lengths. Using RNA interference, McElhinny et al. (2005) demonstrated that nebulin behaves as a 'molecular ruler' in rat cardiac and skeletal muscle. Upon nebulin knockdown, preexisting thin filaments in cultured rat cardiac muscle cells were dramatically elongated from their pointed ends; the barbed ends were unaffected. When the thin filaments were depolymerized, myocytes with decreased nebulin levels reassembled them to unrestricted lengths. Finally, knockdown of nebulin in rat skeletal myotubes revealed its involvement in myofibrillogenesis. McElhinny et al. (2005) concluded that nebulin has a role in specifying and maintaining the length of actin thin filaments in striated muscle.
In mice, Takano et al. (2010) found that Igf1 (147440)-induced phosphatidylinositol 3-kinase-Akt signaling formed a complex of nebulin and N-Wasp (605056) at the Z bands of myofibrils by interfering with glycogen synthase kinase-3-beta (GSK3B; 605004). Although N-Wasp is known to be an activator of the Arp2/3 complex (see 604221) to form branched actin filaments, the nebulin-N-Wasp complex caused actin nucleation for unbranched actin filament formation from the Z bands without the Arp2/3 complex. Furthermore, N-Wasp was required for Igf1-induced muscle hypertrophy. Takano et al. (2010) concluded that their findings presented the mechanisms of IGF1-induced actin filament formation in myofibrillogenesis required for muscle maturation and hypertrophy and a mechanism of actin nucleation.
Nemaline Myopathy 2
In affected members of 5 unrelated families of different ethnic origins with congenital autosomal recessive nemaline myopathy-2 (NEM2; 256030), Pelin et al. (1999) identified 6 different mutations in the NEB gene (161650.0001-161650.0006). All of the mutations were located within the M162-M185 segment. In 2 families with consanguineous parents, the patients were homozygous for point mutations. In 1 family with nonconsanguineous parents, the affected sibs were compound heterozygotes for 2 different mutations, and in 2 further families with 1 detected mutation each, haplotypes were compatible with compound heterozygosity. Immunofluorescence studies with antibodies specific to the C-terminal region of nebulin indicated that the mutations may cause protein truncation possibly associated with loss of fiber-type diversity, which may be relevant to disease pathogenesis.
In 5 affected individuals from 5 Ashkenazi Jewish families with autosomal recessive typical nemaline myopathy, Anderson et al. (2004) identified a 2,502-bp deletion in the NEB gene (ex55del; 161650.0007). Screening for this mutation in a random sample of 4,090 Ashkenazi Jewish individuals revealed a carrier frequency of 1 in 108.
In 7 patients from 4 unrelated Finnish families, 2 of whom were consanguineous, with NEM2 manifest as distal myopathy with onset in childhood or adulthood, Wallgren-Pettersson et al. (2007) identified homozygous missense mutations in the NEB (T5681P, 161650.0008 and S4665I, 161650.0009). The mutations segregated with the disorder in the families from whom DNA was available. Functional studies of the mutation were not performed, but Wallgren-Pettersson et al. (2007) noted that both missense mutations had been found in compound heterozygosity with more disruptive NEB mutations in other families with the more severe typical form of NEM2. The findings suggested that homozygosity for a missense NEB variant may result in a milder myopathic phenotype.
Arthrogryposis Multiplex Congenita 6
In affected infants from 5 unrelated families with arthrogryposis multiplex congenita-6 (AMC6; 619334), Wallgren-Pettersson et al. (2002) identified mutations in the NEB gene. All the mutations were predicted to result in premature termination and a loss of function with absence of the C-terminus of the protein. One of the families of French descent (family 1) had previously been reported by Pelin et al. (1999) (family 3) as having NEM2, but Wallgren-Pettersson et al. (2002) stated that the phenotype was more consistent with AMC6 (see 161650.0003 and 161650.0004).
In 2 brothers with AMC6, Lawlor et al. (2011) identified compound heterozygous loss-of-function mutations in the NEB gene (161650.0012 and 161650.0013). The mutations, which were found by deep sequencing of the NEB gene, segregated with the disorder in the family. Western blot analysis of skeletal muscle tissue from 1 of the patients showed significantly decreased nebulin levels compared to controls. In vitro mechanical studies of patient-derived myofibers showed that they had decreased tension and impaired force generation, which the authors suggested could be explained by altered cross-bridge cycling kinetics. The severe phenotype may correlate with the significant decrease in nebulin protein levels.
Yonath et al. (2012) reported 4 unrelated pregnancies with abnormal prenatal ultrasound findings in fetuses with AMC6. In each family, 1 or both of the parents was of Ashkenazi Jewish descent, and the common exon 55 deletion in the NEB gene (161650.0007) was found in the heterozygous state in the patients and in unaffected parents. A second pathogenic NEB mutation was found in 3 of the patients; a second mutation could not be identified in 1 of the patients.
In twin male fetuses, conceived of consanguineous parents, with AMC6, Todd et al. (2015) identified a homozygous nonsense mutation in the NEB gene (R974X; 161650.0010). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Postmortem examination showed joint contractures, talipes, multiple pterygia, hypertelorism, and cystic hygromas. A previous fetus was therapeutically aborted due to hydrops fetalis at 19 weeks' gestation. Functional studies of the variant and studies of patient cells were not performed. In affected patients from 3 additional families diagnosed with fetal akinesia, a heterozygous splice site, frameshift, or truncating mutation in the NEB gene was found. A second pathogenic mutation was not found in these patients, but there was evidence for autosomal recessive inheritance, suggesting that the affected fetuses carried a second pathogenic variant. Todd et al. (2015) noted the difficulty in screening the nebulin gene for mutations because of its large size and because next-generation sequencing data may not accurately identify pathogenic small copy number variations. These 4 families were ascertained from a cohort of 38 families with severe neuromuscular disease apparent before or at birth.
In 2 sib fetuses with AMC6, Ahmed et al. (2018) identified compound heterozygous nonsense mutations in the NEB gene (Y6262X, 161650.0014 and Y6327X, 161650.0015). The mutations, which were found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The family had previously been reported by Lehtokari et al. (2014). Functional studies of the variants and studies of patient cells were not performed.
In a male fetus, conceived of consanguineous Lebanese parents, with AMC6, Rocha et al. (2021) identified a homozygous splice site mutation in the NEB gene (161650.0016). The mutation, which was found by next-generation sequencing, segregated in the family, with both parents heterozygous carriers. The mutation was not present in the gnomAD database. Functional studies of the variant were not performed.
Donner et al. (2004) found that alternatively spliced exons 143 and 144 of the NEB gene give rise to 2 different transcripts that vary between muscle types and between muscles of different developmental stages. Alternatively spliced exons 166 to 177 express at least 20 different transcripts in adult human tibialis anterior muscle alone. Donner et al. (2004) suggested that the extensive alternative splicing of NEB may explain why nemaline myopathy patients with homozygous truncating mutations show expression of the C terminus of the protein. The use of alternative transcripts may also explain why severe phenotypes are rare among patients with 2 truncating mutations.
Using denaturing high-performance liquid chromatography (DHPLC), Lehtokari et al. (2006) identified 45 novel mutations in the NEB gene in affected members of 44 unrelated families with nemaline myopathy. Mutations were identified in patients representing all clinical categories of disease severity. The majority (55%) of mutations were frameshift or nonsense mutations resulting in premature termination of the protein. Mutations were distributed throughout the gene, with no obvious hotspots. Lehtokari et al. (2006) concluded that mutations in the NEB gene are the most common cause of nemaline myopathy.
In a detailed review and update of 159 families with mutations in the nebulin gene associated with myopathies, Lehtokari et al. (2014) found that the most common types of mutations were splice-site mutations (34%), followed by frameshift (32%), nonsense (23%), and finally missense (7%). The vast majority of patients had compound heterozygous mutations. There were no apparent genotype/phenotype correlations.
Witt et al. (2006) found that Neb -/- mice showed growth retardation 1 day after birth and did not survive beyond week 3. All Neb -/- mice developed a stiff gait and kyphosis, but they could walk up to week 3. Between days 10 and 20, Neb -/- mice developed progressive muscle weakness. Microarray analysis identified 40 differentially expressed genes in Neb -/- mice, and RT-PCR analysis confirmed upregulation of sarcolipin (SLN; 602203), S100a4 (114210), S100a9 (123886), desmoplakin (DSP; 125647), and Ankrd2 (610734). Characterization of skeletal myofibrils showed that absence of Neb caused loss of thin filament length control and pointed end capping in skeletal muscle tissues. However, the genes dysregulated in Neb -/- skeletal muscle were not differentially expressed in Neb -/- myocardium, indicating that nebulin is not a ruler molecule for thin filaments in myocardium. Neb was required to fine-tune calcium-dependent contractility, and consequently, loss of Neb resulted in abnormal calcium sensitivity and Z-disk morphology in skeletal muscle. Furthermore, Neb played important roles in maintaining physiologic Z-disk width and protein composition in skeletal tissues, and its absence led to formation of nemaline bodies and wide Z-disks in mice, recapitulating the phenotype of human nemaline myopathy. Further analysis demonstrated that the C-terminal region of Neb interacted with CapZ (see 601580) and titin (TTN; 188840), thereby linking these 2 ruler molecules implied in Z-disk width specification.
In 2 affected sibs from a British family (family 1) with nemaline myopathy-2 (NEM2; 256030), Pelin et al. (1999) identified a heterozygous 1-bp (G) deletion in exon 165 of the NEB gene, predicted to cause a truncation of the protein at the repeat domain M166. Based on the haplotypes in this family, the authors suspected that the children's maternal allele harbored an as yet unknown NEB mutation. The unaffected father also carried the mutation.
In a Finnish child (family 2) with nemaline myopathy-2 (NEM2; 256030), Pelin et al. (1999) identified a 4-bp (GTTT) duplication/insertion in exon 172 of the NEB gene encoding part of the repeat domains M172 and M173. The child had inherited the mutation from her unaffected mother. The duplication was predicted to cause a frameshift leading to a stop codon in the beginning of exon 173, and truncation of the protein from domain M173. Haplotype analysis suggested that the child had inherited a different, unidentified, mutation from her unaffected father.
In 2 sibs, born of unrelated French parents (family 3) with arthrogryposis multiplex congenita-6 (AMC6; 619334), Pelin et al. (1999) identified compound heterozygous mutations in the NEB gene: a 2-bp (AG) deletion in exon 172 and a 2-bp (GA) deletion in exon 181 (161650.0004). The first mutation would lead to a stop codon in the beginning of exon 173 and a truncation of the protein from domain M173. The second mutation would lead to a stop codon in exon 181 and truncation of the protein from domain M182. Exon 181 is within the alternatively spliced region of NEB, and the maternal mutation may therefore affect only some of the nebulin isoforms. Each unaffected parent was heterozygous for 1 of the mutations, confirming segregation and autosomal recessive inheritance. Although Pelin et al. (1999) reported that these children had nemaline myopathy-2 (NEM2; 256030), Wallgren-Pettersson et al. (2002) stated that, on reexamination, these patients (family 1 in their report) had the severe form of the disorder with arthrogryposis and no spontaneous movements; both infants died in the first weeks of life.
For discussion of the 2-bp (GA) deletion in exon 181 of the NEB gene that was found in compound heterozygous state in 2 infant sibs with arthrogryposis multiple congenita-6 (AMC6; 619334) by Pelin et al. (1999), see 161650.0003.
Pelin et al. (1999) found that a British child with autosomal recessive nemaline myopathy (NEM2; 256030), whose parents were consanguineous (family 5), had a homozygous G-to-T transversion in exon 185 of the NEB gene, resulting in a glu6636-to-ter (E6636X) substitution. The mutation was predicted to result in the loss of the last 134 amino acids of the protein, from the beginning of the serine-rich domain of the C-terminal region of nebulin.
In the only affected child with nemaline myopathy-2 (NEM2; 256030) of a consanguineous German family of Turkish descent (family 4), Pelin et al. (1999) found homozygosity for a G-to-C transversion in the last codon of exon 163 of the NEB gene. The mutation interfered with the 5-prime consensus splice site of intron 163 and was predicted to cause an in-frame skipping of exon 163 or partial retention of intron 163, because of activation of a cryptic splice site 100-bp downstream in intron 163. The latter mRNA had a stop codon 36-bp downstream of exon 163. The abnormally spliced mRNA was seen as 2 distinct RT-PCR products different from the control mRNA.
Nemaline Myopathy 2
In 5 affected individuals from 5 Ashkenazi Jewish families with autosomal recessive typical nemaline myopathy (NEM2; 256030), Anderson et al. (2004) identified a homozygosity for a 2,502-bp deletion completely encompassing exon 55 and parts of introns 54 and 55 of the NEB gene, predicted to result in a transcript encoding 35 fewer amino acids. Screening for this mutation in a random sample of 4,090 Ashkenazi Jewish individuals revealed a carrier frequency of 1 in 108.
Lehtokari et al. (2009) identified the 2,502-bp deletion in 14 of 355 probands with nemaline myopathy from around the world; 2 of the probands had been reported by Anderson et al. (2004). Seven probands were homozygous for the deletion, and 7 carried the mutation in heterozygosity. Two of the families were not of known Ashkenazi Jewish descent, but carried the common haplotype identified in Ashkenazi Jews. The findings were consistent with a founder effect.
Ottenheijm et al. (2009) studied the muscular phenotype of nemaline myopathy patients with NEB exon 55 deletion (NM-NEB). SDS-PAGE and Western blot analysis revealed greatly reduced nebulin levels in skeletal muscle of NM-NEB patients, with the most prominent reduction at nebulin's N-terminal end. Muscle mechanical studies indicated an approximately 60% reduced force generating capacity of NM-NEB muscle and a leftward shift of the force-sarcomere length relation in NM-NEB muscle fibers. This indicates that the mechanism for the force reduction is likely to include shorter and nonuniform thin filament lengths in NM-NEB muscle compared with control muscle. The average thin filament length was reduced from approximately 1.3-micrometer in control muscle to approximately 0.75-micrometer in NM-NEB muscle. Ottenheijm et al. (2009) hypothesized that dysregulated thin filament length may contribute to muscle weakness in nemaline myopathy patients with nebulin mutations.
Arthrogryposis Multiplex Congenita 6
Yonath et al. (2012) reported 4 unrelated pregnancies with abnormal prenatal ultrasound findings in fetuses with arthrogryposis multiplex congenita-6 (AMC6; 619334). In each family, 1 or both of the parents was of Ashkenazi Jewish descent, and the common exon 55 deletion in the NEB gene was found in the heterozygous state in the patients and in unaffected parents. A second pathogenic NEB mutation was found in 3 of the patients; a second mutation could not be identified in 1 of the patients. Prenatal ultrasound showed polyhydramnios, decreased fetal movements, clubfoot, and clenched hands. All patients showed severe hypotonia after birth, and all died within the first months of life.
Feingold-Zadok et al. (2017) identified this mutation in 2 fetal sibs with AMC6 from an Ashkenazi Jewish family (family 1), in compound heterozygosity with a splice site mutation.
In 5 patients from 2 unrelated Finnish families, one of which was consanguineous, with nemaline myopathy-2 (NEM2; 256030) manifest as distal myopathy with onset in childhood or adulthood, Wallgren-Pettersson et al. (2007) identified a homozygous mutation (g.207181A-C, NT_005403) in exon 151 of the NEB gene, resulting in a thr5681-to-pro (T5681P) substitution. The mutation segregated with this disorder in the families and was not found in 300 Finnish control chromosomes. Functional studies of the mutation were not performed, but Wallgren-Pettersson et al. (2007) noted that T5681P had been found in compound heterozygosity with more disruptive NEB mutations in other families with the more typical form of NEM2. The findings suggested that homozygosity for a missense NEB variant may result in a milder myopathic phenotype. Lehtokari et al. (2014) referred to this mutation as THR7417PRO (T7417P), resulting from a c.22249A-C transversion (c.22249A-C, NM_001271208.1), and noted that Marttila et al. (2014) found that the variant reduces the affinity of nebulin for tropomyosin. Marttila et al. (2014) referred to the mutation as THR7382PRO (c.22144A-C, NM_001164507.1).
In 2 unrelated Finnish women, one of which was born of consanguineous parents, with nemaline myopathy-2 (NEM2; 256030) manifest as distal myopathy with onset in childhood or adulthood, Wallgren-Pettersson et al. (2007) identified a homozygous mutation in exon 122 (g.171944G-T, NT_005403) of the NEB gene, resulting in a ser4665-to-ile (S4665I) substitution. The mutation segregated with the disorder in 1 of the families; DNA was not available from other members of the second family. The mutation was not found in 188 Finnish control chromosomes nor in 90 additional control chromosomes from the same geographic region. Functional studies of the variant were not performed, but Wallgren-Pettersson et al. (2007) noted that S4665I had been found in compound heterozygosity with more disruptive NEB mutations in other families with the more typical form of NEM2. The findings suggested that homozygosity for a missense NEB variant may result in a milder myopathic phenotype. Lehtokari et al. (2014) referred to this mutation as SER6366ILE (S6366I), resulting from a c.19097G-T transversion (c.19097G-T, NM_001271208.1) and noted that Marttila et al. (2014) found that the variant increases nebulin-actin affinity.
Lehtokari et al. (2014) reported another Finnish patient with distal nemaline myopathy who was compound heterozygous for the S6366I mutation and a splice site variant in the NEB gene.
In twin male fetuses, conceived of consanguineous parents (family 9), with arthrogryposis multiplex congenita-6 (AMC6; 619334) presenting as fetal akinesia with lethal multiple pterygia syndrome, Todd et al. (2015) identified a homozygous c.2920C-T transition (c.2920C-T, NM_001164508) in exon 29 of the NEB gene, predicted to result in an arg974-to-ter (R974X) substitution. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the ExAC database. Postmortem examination showed joint contractures, talipes, multiple pterygia, hypertelorism, and cystic hygromas. A previous fetus was therapeutically aborted due to hydrops fetalis at 19 weeks' gestation. Functional studies of the variant and studies of patient cells were not performed.
In a male fetus, conceived of consanguineous Egyptian parents, with arthrogryposis multiplex congenita-6 (AMC6; 619334), Abdalla et al. (2017) identified a homozygous G-to-T transversion in intron 74 of the NEB gene (c.10872+1G-T, ENST00000427231.2). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to disrupt an essential splice site. A similarly affected fetus from this family was therapeutically aborted at 20 weeks' gestation; DNA was not available from that patient.
In 2 brothers with arthrogryposis multiplex congenita-6 (AMC6; 619334), Lawlor et al. (2011) identified compound heterozygous loss-of-function mutations in the NEB gene: a G-to-T transversion in intron 13 (c.1152+1G-T, NG_009382.1), predicted to result in a splice site alteration, and a 2-bp deletion in exon 81 (c.11318_11319delAG; 161650.0013), predicted to result in a frameshift and premature termination (Lys3774ArgfsTer10). The mutations, which were found by deep sequencing of the NEB gene, segregated with the disorder in the family. Neither mutation was present in 236 control chromosomes. Western blot analysis of skeletal muscle from 1 of the patients showed significantly decreased nebulin levels compared to controls. In vitro mechanical studies of patient-derived myofibers showed that they had decreased tension and impaired force generation, which the authors suggested could be explained by altered cross-bridge cycling kinetics. The severe phenotype may correlate with the significant decrease in nebulin protein levels.
For discussion of the 2-bp deletion in exon 81 of the NEB gene (c.11318_11319delAG, NG_009382.1), predicted to result in a frameshift and premature termination (Lys3774ArgfsTer10), that was found in compound heterozygous state in 2 brothers with arthrogryposis multiplex congenita-6 (AMC6; 619334) by Lawlor et al. (2011), see 161650.0012.
In 2 sib fetuses with arthrogryposis multiplex congenita-6 (AMC6; 619334), Ahmed et al. (2018) identified compound heterozygous nonsense mutations in the NEB gene: a c.18786C-G transversion (c.18786C-G, NM_001271208.1), resulting in a tyr6262-to-ter (Y6262X) substitution, and a c.18981C-G transversion, resulting in a tyr6327-to-ter (Y6327X; 161650.0015) substitution. The mutations, which were found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The family had previously been reported by Lehtokari et al. (2014). Functional studies of the variants were not performed.
For discussion of the c.18981C-G transversion (c.18981C-G, NM_001271208.1) in the NEB gene, resulting in a tyr6327-to-ter (Y6327X) substitution, that was found in compound heterozygous state in 2 sib fetuses with arthrogryposis multiplex congenita-6 (AMC6; 619334) by Ahmed et al. (2018), see 161650.0014.
In a male fetus, conceived on consanguineous Lebanese parents, with arthrogryposis multiplex congenita-6 (AMC6; 619334), Rocha et al. (2021) identified a homozygous G-to-T transition in intron 22 (c.19102-1G-T, NM_001164508) of the NEB gene, predicted to result in a splicing defect. The mutation, which was found by next-generation sequencing, segregated in the family, with both parents heterozygous carriers. The mutation was not present in the gnomAD database. Functional studies of the variant were not performed.
Abdalla, E., Ravenscroft, G., Zayed, L., Beecroft, S. J., Laing, N. G. Lethal multiple pterygium syndrome: a severe phenotype associated with a novel mutation in the nebulin gene. Neuromusc. Disord. 27: 537-541, 2017. [PubMed: 28336317] [Full Text: https://doi.org/10.1016/j.nmd.2017.01.013]
Ahmed, A. A., Skaria, P., Safina, N. P., Thiffault, I., Kats, A., Taboada, E., Habeebu, S., Saunders, C. Arthrogryposis and pterygia as lethal end manifestations of genetically defined congenital myopathies. Am. J. Med. Genet. 176A: 359-367, 2018. [PubMed: 29274205] [Full Text: https://doi.org/10.1002/ajmg.a.38577]
Anderson, S. L., Ekstein, J., Donnelly, M. C., Keefe, E. M., Toto, N. R., LeVoci, L. A., Rubin, B. Y. Nemaline myopathy in the Ashkenazi Jewish population is caused by a deletion in the nebulin gene. Hum. Genet. 115: 185-190, 2004. [PubMed: 15221447] [Full Text: https://doi.org/10.1007/s00439-004-1140-8]
Donner, K., Sandbacka, M., Lehtokari, V.-L., Wallgren-Pettersson, C., Pelin, K. Complete genomic structure of the human nebulin gene and identification of alternatively spliced transcripts. Europ. J. Hum. Genet. 12: 744-751, 2004. [PubMed: 15266303] [Full Text: https://doi.org/10.1038/sj.ejhg.5201242]
Feingold-Zadok, M., Chitayat, D., Chong, K., Injeyan, M., Shannon, P., Chapmann, D., Maymon, R., Pillar, N., Reish, O. Mutations in the NEB gene cause fetal akinesia/arthrogryposis multiplex congenita. Prenatal Diag. 37: 144-150, 2017. [PubMed: 27933661] [Full Text: https://doi.org/10.1002/pd.4977]
Labeit, S., Kolmerer, B. The complete primary structure of human nebulin and its correlation to muscle structure. J. Molec. Biol. 248: 308-315, 1995. [PubMed: 7739042] [Full Text: https://doi.org/10.1016/s0022-2836(95)80052-2]
Lawlor, M. W., Ottenheijm, C. A., Lehtokari, V.-L., Cho, K., Pelin, K., Wallgren-Pettersson, C., Granzier, H., Beggs, A. H. Novel mutations in NEB cause abnormal nebulin expression and markedly impaired muscle force generation in severe nemaline myopathy. Skeletal Muscle 1: 23, 2011. [PubMed: 21798101] [Full Text: https://doi.org/10.1186/2044-5040-1-23]
Lehtokari, V.-L., Greenleaf, R. S., DeChene, E. T., Kellinsalmi, M., Pelin, K., Laing, N. G., Beggs, A. H., Wallgren-Pettersson, C. The exon 55 deletion in the nebulin gene--one single founder mutation with world-wide occurrence. Neuromusc. Disord. 19: 179-181, 2009. [PubMed: 19232495] [Full Text: https://doi.org/10.1016/j.nmd.2008.12.001]
Lehtokari, V.-L., Kiiski, K., Sandaradura, S. A., Laporte, J., Repo, P., Frey, J. A., Donner, K., Marttila, M., Saunders, C., Barth, P. G., den Dunnen, J. T., Beggs, A. H., Clarke, N. F., North, K. N., Laing, N. G., Romero, N. B., Winder, T. L., Pelin, K., Wallgren-Pettersson, C. Mutation update: the spectra of nebulin variants and associated myopathies. Hum. Mutat. 35: 1418-1426, 2014. [PubMed: 25205138] [Full Text: https://doi.org/10.1002/humu.22693]
Lehtokari, V.-L., Pelin, K., Sandbacka, M., Ranta, S., Donner, K., Muntoni, F., Sewry, C., Angelini, C., Bushby, K., Van den Bergh, P., Iannaccone, S., Laing, N. G., Wallgren-Pettersson, C. Identification of 45 novel mutations in the nebulin gene associated with autosomal recessive nemaline myopathy. Hum. Mutat. 27: 946-956, 2006. [PubMed: 16917880] [Full Text: https://doi.org/10.1002/humu.20370]
Limongi, M. Z., Pelliccia, F., Rocchi, A. Assignment of the human nebulin gene (NEB) to chromosome band 2q24.2 and the alpha-1 (III) collagen gene (COL3A1) to chromosome band 2q32.2 by in situ hybridization: the FRA2G common fragile site lies between the two genes in the 2q31 band. Cytogenet. Cell Genet. 77: 259-260, 1997. [PubMed: 9284930] [Full Text: https://doi.org/10.1159/000134590]
Marttila, M., Hanif, M., Lemola, E., Nowak, K. J., Laitila, J., Gronholm, M., Wallgren-Pettersson, C., Pelin, K. Nebulin interactions with actin and tropomyosin are altered by disease-causing mutations. Skeletal Muscle 4: 15, 2014. Note: Electronic Article. [PubMed: 25110572] [Full Text: https://doi.org/10.1186/2044-5040-4-15]
McElhinny, A. S., Schwach, C., Valichnac, M., Mount-Patrick, S., Gregorio, C. C. Nebulin regulates the assembly and lengths of the thin filaments in striated muscle. J. Cell Biol. 170: 947-957, 2005. [PubMed: 16157704] [Full Text: https://doi.org/10.1083/jcb.200502158]
Ottenheijm, C. A. C., Witt, C. C., Stienen, G. J., Labeit, S., Beggs, A. H., Granzier, H. Thin filament length dysregulation contributes to muscle weakness in nemaline myopathy patients with nebulin deficiency. Hum. Molec. Genet. 18: 2359-2369, 2009. [PubMed: 19346529] [Full Text: https://doi.org/10.1093/hmg/ddp168]
Pelin, K., Hilpela, P., Donner, K., Sewry, C., Akkari, P. A., Wilton, S. D., Wattanasirichaigoon, D., Bang, M.-L., Centner, T., Hanefeld, F., Odent, S., Fardeau, M., Urtizberea, J. A., Muntoni, F., Dubowitz, V., Beggs, A. H., Laing, N. G., Labeit, S., de la Chapelle, A., Wallgren-Pettersson, C. Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy. Proc. Nat. Acad. Sci. 96: 2305-2310, 1999. [PubMed: 10051637] [Full Text: https://doi.org/10.1073/pnas.96.5.2305]
Pelin, K., Ridanpaa, M., Donner, K., Wilton, S., Krishnarajah, J., Laing, N., Kolmerer, B., Millevoi, S., Labeit, S., de la Chapelle, A., Wallgren-Pettersson, C. Refined localisation of the genes for nebulin and titin on chromosome 2q allows the assignment of nebulin as a candidate gene for autosomal recessive nemaline myopathy. Europ. J. Hum. Genet. 5: 229-234, 1997. [PubMed: 9359044]
Rocha, M. L., Dittmayer, C., Uruha, A., Korinth, D., Chaoui, R., Schlembach, D., Rossi, R., Pelin, K., Suk, E. K., Schmid, S., Goebel, H. H., Schuelke, M., Stenzel, W., Englert, B. A novel mutation in NEB causing foetal nemaline myopathy with arthrogryposis during early gestation. Neuromusc. Disord. 31: 239-245, 2021. [PubMed: 33376055] [Full Text: https://doi.org/10.1016/j.nmd.2020.11.014]
Schurr, E., Skamene, E., Gros, P. Mapping of the gene coding for the muscle protein nebulin (Neb) to the proximal region of mouse chromosome 2. Cytogenet. Cell Genet. 57: 214-216, 1991. [PubMed: 1683831] [Full Text: https://doi.org/10.1159/000133150]
Stedman, H., Browning, K., Oliver, N., Oronzi-Scott, M., Fischbeck, K., Sarkar, S., Sylvester, J., Schmickel, R., Wang, K. Nebulin cDNAs detect a 25-kilobase transcript in skeletal muscle and localize to human chromosome 2. Genomics 2: 1-7, 1988. [PubMed: 2838409] [Full Text: https://doi.org/10.1016/0888-7543(88)90102-4]
Takano, K., Watanabe-Takano, H., Suetsugu, S., Kurita, S., Tsujita, K., Kimura, S., Karatsu, T., Takenawa, T., Endo, T. Nebulin and N-WASP cooperate to cause IGF-1-induced sarcomeric actin filament formation. Science 330: 1536-1540, 2010. [PubMed: 21148390] [Full Text: https://doi.org/10.1126/science.1197767]
Todd, E. J., Yau, K. S., Ong, R., Slee, J., McGillivray, G., Barnett, C. P., Haliloglu, G., Talim, B., Akcoren, Z., Kariminejad, A., Cairns, A., Clarke, N. F., and 14 others. Next generation sequencing in a large cohort of patients presenting with neuromuscular disease before or at birth. Orphanet J. Rare Dis. 10: 148, 2015. Note: Electronic Article. [PubMed: 26578207] [Full Text: https://doi.org/10.1186/s13023-015-0364-0]
Wallgren-Pettersson, C., Donner, K., Sewry, C., Bijlsma, E., Lammens, M., Bushby, K., Giovannucci Uzielli, M. L., Lapi, E., Odent, S., Akcoren, Z., Topaloglu, H., Pelin, K. Mutations in the nebulin gene can cause severe congenital nemaline myopathy. Neuromusc. Disord. 12: 674-679, 2002. [PubMed: 12207937] [Full Text: https://doi.org/10.1016/s0960-8966(02)00065-2]
Wallgren-Pettersson, C., Lehtokari, V.-L., Kalimo, H., Paetau, A., Nuutinen, E., Hackman, P., Sewry, C., Pelin, K., Udd, B. Distal myopathy caused by homozygous missense mutations in the nebulin gene. Brain 130: 1465-1476, 2007. [PubMed: 17525139] [Full Text: https://doi.org/10.1093/brain/awm094]
Wang, K., Knipfer, M., Huang, Q.-Q., van Heerden, A., Hsu, L. C.-L., Gutierrez, G., Quian, X.-L., Stedman, H. Human skeletal muscle nebulin sequence encodes a blueprint for thin filament architecture: sequence motifs and affinity profiles of tandem repeats and terminal SH3. J. Biol. Chem. 271: 4304-4314, 1996. [PubMed: 8626778] [Full Text: https://doi.org/10.1074/jbc.271.8.4304]
Witt, C. C., Burkart, C., Labeit, D., McNabb, M., Wu, Y., Granzier, H., Labeit, S. Nebulin regulates thin filament length, contractility, and Z-disk structure in vivo. EMBO J. 25: 3843-3855, 2006. [PubMed: 16902413] [Full Text: https://doi.org/10.1038/sj.emboj.7601242]
Yonath, H., Reznik-Wolf, H., Berkenstadt, M., Eisenberg-Barzilai, S., Lehtokari, V.-L., Wallgren-Pettersson, C., Mehta, L., Achiron, R., Gilboa, Y., Polak-Charcon, S., Winder, T., Frydman, M., Pras, E. Carrier state for the nebulin exon 55 deletion and abnormal prenatal ultrasound findings as potential signs of nemaline myopathy. Prenatal Diag. 32: 70-74, 2012. [PubMed: 22367672] [Full Text: https://doi.org/10.1002/pd.2905]
Zeviani, M., Darras, B. T., Rizzuto, R., Salviati, G., Betto, R., Bonilla, E., Miranda, A. F., Du, J., Samitt, C., Dickson, G., Walsh, F. S., DiMauro, S., Francke, U., Schon, E. A. Cloning and expression of human nebulin cDNAs and assignment of the gene to chromosome 2q31-q32. Genomics 2: 249-256, 1988. [PubMed: 3397062] [Full Text: https://doi.org/10.1016/0888-7543(88)90009-2]