New UBA1 Mutation Linked to Atypical SBMA in Iranian Family

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by Marta Figueiredo PhD |

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A new mutation in the UBEA1 gene was identified as the cause of an atypical form of spinal and bulbar muscular atrophy (SBMA), or Kennedy’s disease, in four men of an Iranian family, a study shows.

While UBEA1 mutations are typically associated with X-linked infantile spinal muscular atrophy (SMA), which is a rare form of SMA that affects boys before or shortly after birth, the four affected men developed symptoms in their midlife — an onset that more closely resembles SBMA.

Researchers decided to call the disease “non-Kennedy SBMA” because, while resembling SBMA, it was not associated with mutations in the androgen receptor (AR) gene — the underlying genetic cause of SBMA.

The study, “Identification of UBA1 as the causative gene of an X-linked non-Kennedy SBMA,” was published in the European Journal of Neurology.

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SMA is a genetic disease characterized by the progressive loss of lower motor neurons, the specialized nerve cells that relay voluntary movement signals from the spinal cord to muscles. This loss causes muscle weakness and atrophy, among other symptoms.

While its five main types — 0, 1, 2, 3, and 4 — are caused by mutations in a gene called SMN1, rarer types are linked to mutations in other genes.

Two of these rarer forms, SBMA and X-linked infantile SMA, affect males almost exclusively because they involve mutations in genes located in the X chromosome (one of the two sex chromosomes).

This means that males who inherit the mutated gene will develop the condition, as they only have one X chromosome (inherited from the mother). In females — who have two X chromosomes, one from the mother and one from the father — the healthy gene copy can compensate for the mutated copy. These females most likely will not show any disease symptoms, but they will still have a 50% chance of having a son with the condition, and a 50% risk of having a daughter who will also be a carrier.

SBMA is an adult-onset form of the disease that progresses very slowly. It is linked to mutations in the AR gene, which encodes the receptor protein of androgens, a group of hormones that are important for normal male sexual development.

The resulting abnormal receptor protein is thought to accumulate to toxic levels inside motor neurons, triggering their death.

Symptoms usually begin between 30 and 50 years of age, and initially affect muscles of the legs and arms, following by bulbar muscles, which are those involved in swallowing, chewing, and speech.

Patients also show signs of male sex hormone deficiency, and sensory problems are commonly reported. They have a normal life expectancy and usually don’t develop respiratory problems.

UBA1 mutation most likely cause of SBMA in 2 brothers, 2 cousins

Now, a team of researchers in Iran described the case of four related men with SBMA symptoms, but no AR mutations.

All four — two brothers and two of their cousins — were born from unaffected parents, with their mothers being sisters. Detailed clinical data was available for three of the men.

All three developed the first symptoms, muscle weakness in the feet, between the ages of 42 and 53 years. Motor impairment was progressive and consistent with lower motor damage in the limbs and cranial, including bulbar, muscles. In addition, they showed symptoms and signs of damage in the nerves that relay messages related to sensations.

The men reported no respiratory problems at rest or during activity, and had no obvious signs of male sex hormone deficiency.

While some of these features excluded other motor neuron diseases and supported an SBMA diagnosis, the absence of hormonal abnormalities did not. In addition, previous genetic testing revealed no mutations in the AR gene.

The researchers then conducted further genetic testing in two affected cousins and several non-affected family members.

By analyzing the location and pattern of inheritance of detected mutations, as well as whether they would likely have damaging effects, the team identified a new UBA1 mutation as the most likely cause of the disease.

The UBA1 gene provides the instructions to produce an enzyme of the same name that is essential for breaking down damaged or no-longer-needed proteins inside cells. These mutations are thought to result in the toxic buildup of waste material that affects motor neurons, which die as a consequence.

The newly discovered mutation, c.1499C>T, resulted in an amino acid change in the resulting UBA1 enzyme sequence and was classified as damaging or likely disease-causing. (Amino acids are the building blocks of protein).

In addition, the mutation was absent from several databases of healthy individuals and the amino acid affected by it was highly conserved across several species, suggesting it may be essential for the protein’s function.

Notably, four other mutations in the UBA1 gene have been identified as the cause of X-linked infantile SMA, a very rare and severe form of SMA. That type is characterized by a symptom onset before or shortly after birth, rapidly progressive muscle weakness, and reduced life expectancy.

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Observed sensory problems pointed to an atypical form of SBMA

Additional analysis revealed that these mutations and the newly identified variant affect amino acids in the same domain of the encoded enzyme and result in structural changes that may affect UBA1’s binding to other molecules.

These findings suggest that amino acid changes in that domain of UBA1 “may promote motor neuron dysfunctions and disease,” the researchers wrote.

They also noted that while the presence of a UBA1 mutation in these patients could suggest a very-late onset form of X-linked infantile SMA, the observed sensory problems pointed to an atypical form of SBMA.

“All in all, the clinical and genetic findings pertaining to [these patients] are yet another indication of the complexities and overlaps among various neurologic diseases,” the researchers wrote.

“Here, these issues are imperfectly resolved by designating the name ‘non-Kennedy SBMA,’ ” they added.

Future studies are needed to better understand how this new UBA1 mutation leads to the development of the atypical form of SBMA and how these mechanisms differ from those of other UBA1 mutations linked to X-linked infantile SMA.

The post New UBA1 Mutation Linked to Atypical SBMA in Iranian Family appeared first on SMA News Today.