Spinal and Bulbar Muscular Atrophy (AR)
| Dred_ID | RD00007 |
| OMIM ID | 313200 |
| Disease name | Spinal and Bulbar Muscular Atrophy |
| Alternative names | Spinal and Bulbar Muscular Atrophy Sbma Kennedy Disease Kennedy Spinal and Bulbar Muscular Atrophy Bulbospinal Muscular Atrophy, X-linked Bulbospinal Neuronopathy, X-linked Recessive Spinal and Bulbar Muscular Atrophy, X-linked 1 Smax1 Xbsn |
| Category | Genetic diseases, Rare diseases, Neuronal diseases, Reproductive diseases, Muscle diseases |
| Phenotype | NIH Rare Diseases: Kennedy disease is a gradually progressive, neuromuscular disorder characterized by wasting of the proximal muscles (those closer to the trunk) and bulbar muscles (those of the face and throat).The condition mainly affects males, with onset between the ages of 30 and 60. Early symptoms may include tremor, muscle cramps, and muscle twitching. This is followed by progressive muscle weakness and wasting, which may manifest in a variety of ways. Affected people may also have gynecomastia, testicular atrophy (reduction in size or function of the testes), and reduced fertility as a result of mild androgen insensitivity. Kennedy disease is caused by a mutation in the androgen receptor (AR) gene and is inherited in an X-linked recessive manner. Treatment may include physiotherapy and rehabilitation; medications to alleviate tremor and muscle cramps; and hormone therapy or surgical treatment for gynecomastia.
OMIM: Kennedy disease is an X-linked recessive form of spinal muscular atrophy. It occurs only in men. Age at onset is usually in the third to fifth decade of life, but earlier involvement has been reported. The disorder is characterized by slowly progressive limb and bulbar muscle weakness with fasciculations, muscle atrophy, and gynecomastia (Harding et al., 1982). The disorder is clinically similar to, but genetically distinct from, classic forms of autosomal spinal muscular atrophy. |
| Miscellaneouse | OMIM: prevalence of 1 in 40,000 slow progression onset usually between 30 and 50 years of age mild symptoms may occur in teenage years childhood onset has been reported allelic disorder to androgen insensitivity syndrome |
| Prevalence | Prevalence: 1-9/1000000 (Italy),1-9/100000 (Italy) [source: MalaCards] |
| Inheritance | X-linked recessive |
| Anticipation | Yes |
| Evidence | Strong |
| Gene symbol | AR |
| Alias symbols | KD; AIS; TFM; DHTR; SBMA; HYSP1; NR3C4; SMAX1; HUMARA |
| Gene name | androgen receptor |
| Gene map locus | Xq12; chrX:67,544,021-67,730,619(+) |
| Ensembl Gene ID | ENSG00000169083 |
| Gene expression and Gene Ontology | BioGPS |
| Protein expression | Human Protein Atlas |
| Gene sequence | Sequence |
| Variation | ClinVar, dbSNP | Gene conservation | Gene Conservation from UCSC Genome Browser |
| Gene Description | The androgen receptor gene is more than 90 kb long and codes for a protein that has 3 major functional domains: the N-terminal domain, DNA-binding domain, and androgen-binding domain. The protein functions as a steroid-hormone activated transcription factor. Upon binding the hormone ligand, the receptor dissociates from accessory proteins, translocates into the nucleus, dimerizes, and then stimulates transcription of androgen responsive genes. This gene contains 2 polymorphic trinucleotide repeat segments that encode polyglutamine and polyglycine tracts in the N-terminal transactivation domain of its protein. Expansion of the polyglutamine tract from the normal 9-34 repeats to the pathogenic 38-62 repeats causes spinal bulbar muscular atrophy (Kennedy disease). Mutations in this gene are also associated with complete androgen insensitivity (CAIS). Two alternatively spliced variants encoding distinct isoforms have been described. [provided by RefSeq, Jan 2017] |
| Repeat unit | CAG |
| Normal repeat copies | 9-36 |
| Pathogenic repeat copies | ≥39 |
| Gene | AR |
| Repeat location | CDS |
| Chromosome locus | chrX:67545318-67545386 (+) |
| Repeat conservation | Repeat Conservation from UCSC Genome Browser |
| Toxic cause | Protein |
| Possible toxicity | By postmortem examination of 5 SBMA patients, Banno et al. (2006) found that the degree of mutant AR accumulation in spinal motor neurons correlated to that of scrotal skin epithelial cells. Mutant AR accumulation also correlated with CAG repeat length and disease severity. Scrotal biopsies from 13 additional patients also correlated with CAG repeat length and disease severity. In 5 additional SBMA patients who received subcutaneous leuprorelin injections, mutant AR protein was decreased in scrotal skin biopsies. After 24 weeks of treatment, there were no significant motor function changes, but 3 patients expressed subjective improvement. Banno et al. (2006) concluded that scrotal skin biopsy findings may be a biomarker of SBMA and could be used in therapeutic clinical trials. [By OMIM] |
| Pathway annotation | Reactome, KEGG |
| PMID | 19279159 |
| Authors | Montie HL, Cho MS, Holder L, Liu Y, Tsvetkov AS, Finkbeiner S, Merry DE |
| Title | Cytoplasmic retention of polyglutamine-expanded androgen receptor ameliorates disease via autophagy in a mouse model of spinal and bulbar muscular atrophy |
| Journal | Hum Mol Genet. 18(11):1937-50 |
| Year | 2009 |
| PMID | 16358333 |
| Authors | Banno H, Adachi H, Katsuno M, Suzuki K, Atsuta N, Watanabe H, Tanaka F, Doyu M, Sobue G |
| Title | Mutant androgen receptor accumulation in spinal and bulbar muscular atrophy scrotal skin: a pathogenic marker |
| Journal | Ann Neurol. 59(3):520-6 |
| Year | 2006 |