Alternative titles; symbols
ORPHA: 319332; DO: 0080979;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6q25.2 | Arthrogryposis multiplex congenita 3, myogenic type | 618484 | Autosomal recessive | 3 | SYNE1 | 608441 |
A number sign (#) is used with this entry because of evidence that myogenic-type arthrogryposis multiplex congenita-3 (AMC3) is caused by homozygous or compound heterozygous mutation in the SYNE1 gene (608441) on chromosome 6q25.
Myogenic-type arthrogryposis multiplex congenita-3 (AMC3) is an autosomal recessive disorder characterized by decreased fetal movements, hypotonia, variable skeletal defects, including clubfoot and scoliosis, and delayed motor milestones with difficulty walking (summary by Baumann et al., 2017).
Attali et al. (2009) reported a consanguineous Palestinian family in which 2 sibs had a disorder characterized by decreased fetal movements, hypotonia, bilateral clubfoot, and delayed motor milestones. They had progressive motor decline with loss of ambulation after the first decade, and both developed kyphosis and/or scoliosis. One patient was noted to have normal intelligence. The older sib died of restrictive lung disease at age 22 years. Muscle biopsies in affected individuals revealed variation in size of muscle fibers without necrosis or fibrosis. Neither had cerebellar or pyramidal signs. A brother of these sibs married a cousin and had 2 affected pregnancies. Prenatal ultrasound showed clubfoot and decreased fetal movements; both pregnancies were terminated. Attali et al. (2009) described the disorder as a myogenic arthrogryposis.
Laquerriere et al. (2014) identified 2 sibs, born of consanguineous parents (family K168) with AMC3. Clinical details were limited, but the proband was noted to have onset in utero; there were no additional features noted.
Baumann et al. (2017) reported an 8-year-old boy, born of consanguineous Turkish parents, with AMC3. There were reduced fetal movements during pregnancy and the infant was small for gestational age. At birth, he showed severe muscle weakness and arthrogryposis, including adducted thumbs, flexion contractures of fingers, and clubfeet; he also had cryptorchidism. He was able to walk unsupported at the age of 2 years, but showed the Gowers maneuver and had limited ability to walk long distances or climb stairs at age 8. He had marked proximal muscular weakness, reduced deep tendon reflexes, mild facial weakness, and flexion contractures of some proximal interphalangeal joints. There was neither pyramidal nor cerebellar involvement. Additional features included hyperopia, intermittent strabismus, and impaired intellectual development. Muscle ultrasound showed fibrosis and fatty replacement of muscle tissue; muscle biopsy showed variation in fiber size, centralized nuclei, and abnormalities of the nuclear membrane. There was no cardiac involvement and serum creatine kinase was normal. Family history revealed that an older brother had presented with severe muscular hypotonia at birth and died at the age of 4 months from respiratory failure.
The transmission pattern of AMC3 in the family reported by Attali et al. (2009) was consistent with autosomal recessive inheritance.
By genomewide linkage analysis in a consanguineous Palestinian family segregating an autosomal recessive form of AMC, Attali et al. (2009) found linkage to chromosome 6q25.
In affected members of a Palestinian family with AMC3, Attali et al. (2009) identified a homozygous splice site mutation (608441.0011) in the distal region of the SYNE1 gene.
In 2 sibs, born of consanguineous parents (family K168) with AMC3, Laquerriere et al. (2014) identified a homozygous nonsense mutation in the SYNE1 gene (R8193X; 608441.0018). The mutation, which was found by a combination of genetic mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The authors suggested that the disorder was due to skeletal muscle involvement rather than axoglial. The family was ascertained from a cohort of 63 patients from 31 multiplex and/or consanguineous families with unexplained nonsyndromic AMC who underwent exome sequencing.
In an 8-year-old boy, born of consanguineous Turkish parents, with AMC3, Baumann et al. (2017) identified a homozygous truncating mutation at the C terminus of the SYNE1 gene (R8746X; 608441.0019). The mutation affected both the short muscle-specific KASH-containing isoform nesprin-1-alpha-2 and the CNS-expressed giant isoform. The mutation, which was found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family. Analysis of patient cells showed that the mutant mRNA was expressed at normal levels, suggesting that normal levels of the truncated protein were expressed. Baumann et al. (2017) suggested that loss of the KASH domain in SYNE1 is sufficient to cause AMC3. Baumann et al. (2017) noted that the few reported SYNE1 nonsense or splice site mutations identified in patients with AMC3 all terminate in the C-terminal KASH domain and would be expected to affect at least the major muscle-specific nesprin-1-alpha-2 isoform. Thus, loss of this KASH domain is sufficient to cause AMC3.
Puckelwartz et al. (2009) generated mice with C-terminal deletion of Syne1, including the KASH domain. Mice homozygous for this mutation died at or near birth from respiratory failure, whereas surviving mice displayed hindlimb weakness and an abnormal gait. With increasing age, kyphoscoliosis, muscle pathology, and cardiac conduction defects developed. The protein components of the LINC complex, including mutant nesprin-1-alpha-2, lamin A/C, and Sun2 (Unc84b), were localized at the nuclear membrane in mutant mouse skeletal muscle myofibers; however, mutant nesprin-1 interaction with Sun2 was disrupted in primary myoblasts, resulting from loss of the C-terminal KASH domain.
Pearson and Fowler (1963) reported 2 sibs with a skeletal muscle disorder leading to arthrogryposis in early childhood. The proband was a 10-year-old boy born with bilateral clubfeet and dislocation of the right hip. He showed delayed motor development with swallowing difficulties and progressive muscle weakness until about age 7, when the muscle weakness stabilized. He had poor head control, contractures of the limbs, and was unable to stand without support. His 6-year-old sister had a similar disease course and could not run, although she could walk with a waddling gait. Skeletal muscle biopsy in both sibs showed marked fiber size variation, internalized nuclei, and presence of vacuoles. The maternal grandparents were first cousins, suggesting autosomal recessive inheritance. The findings were consistent with myogenic arthrogryposis. A similar situation may have existed in 2 sibs reported by Banker et al. (1957) who both died in infancy. One sibs had arthrogryposis, whereas the younger sib had flaccid hypotonia without contractures. Postmortem examination was consistent with a primary myopathy with features of a progressive muscular dystrophy.
Attali, R., Warwar, N., Israel, A., Gurt, I., McNally, E., Puckelwartz, M., Glick, B., Nevo, Y., Ben-Neriah, Z., Melki, J. Mutation of SYNE-1, encoding an essential component of the nuclear lamina, is responsible for autosomal recessive arthrogryposis. Hum. Molec. Genet. 18: 3462-3469, 2009. [PubMed: 19542096] [Full Text: https://doi.org/10.1093/hmg/ddp290]
Banker, B. Q., Victor, M., Adams, R. D. Arthrogryposis multiplex due to progressive muscular dystrophy. Brain 80: 319-334, 1957. [PubMed: 13471804] [Full Text: https://doi.org/10.1093/brain/80.3.319]
Baumann, M., Steichen-Gersdorf, E., Krabichler, B., Petersen, B.-S., Weber, U., Schmidt, W. M., Zschocke, J., Muller, T., Bittner, R. E., Janecke, A. R. Homozygous SYNE1 mutation causes congenital onset of muscular weakness with distal arthrogryposis: a genotype-phenotype correlation. Europ. J. Hum. Genet. 25: 262-266, 2017. [PubMed: 27782104] [Full Text: https://doi.org/10.1038/ejhg.2016.144]
Laquerriere, A., Maluenda, J., Camus, A., Fontenas, L., Dieterich, K., Nolent, F., Zhou, J., Monnier, N., Latour, P., Gentil, D., Heron, D., Desguerres, I., and 48 others. Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects. Hum. Molec. Genet. 23: 2279-2289, 2014. [PubMed: 24319099] [Full Text: https://doi.org/10.1093/hmg/ddt618]
Pearson, C. M., Fowler, W. M., Jr. Hereditary non-progressive muscular dystrophy inducing arthrogryposis syndrome. Brain 86: 75-88, 1963. [PubMed: 13942250] [Full Text: https://doi.org/10.1093/brain/86.1.75]
Puckelwartz, M. J., Kessler, E., Zhang, Y., Hodzic, D., Randles, K. N., Morris, G., Earley, J. U., Hadhazy, M., Holaska, J. M., Mewborn, S. K., Pytel, P., McNally, E. M. Disruption of nesprin-1 produces an Emery-Dreifuss muscular dystrophy-like phenotype in mice. Hum. Molec. Genet. 18: 607-620, 2009. [PubMed: 19008300] [Full Text: https://doi.org/10.1093/hmg/ddn386]