Amyotrophic Lateral Sclerosis 23
A number sign (#) is used with this entry because of evidence that amyotrophic lateral sclerosis-23 (ALS23) is caused by heterozygous mutation in the ANXA11 gene (602572) on chromosome 10q22.
For a phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400).
Clinical FeaturesSmith et al. (2017) reported 10 patients from 7 unrelated families with familial ALS and 3 unrelated patients with sporadic ALS associated with ANXA11 mutations. The patients had late onset (range, 50 to 83 years; average, 67 years) of classic ALS disease symptoms without dementia, and both bulbar and limb onset occurred. Postmortem examination of 1 patient showed marked neuronal loss within the anterior horn of the spinal cord and myelin pallor and astrogliosis in the anterior and lateral corticospinal tracts. Many surviving motor neurons contained cytoplasmic inclusions that stained positive for p62 (601530) and TDP43 (605078).
InheritanceThe transmission pattern of ALS23 in the families reported by Smith et al. (2017) was consistent with autosomal dominant inheritance with incomplete penetrance.
Molecular GeneticsIn 10 patients from 7 unrelated families with ALS23, Smith et al. (2017) identified 4 different heterozygous missense mutations in the ANXA11 gene (see, e.g., D40G, 602572.0001, G38R, 602572.0002; and G175R, 602572.0003). Three patients with sporadic ALS were also found to carry heterozygous missense variants (D40G, G189E, and R235Q). The mutations were found by whole-exome sequencing of 751 probands with familial ALS (FALS) and direct sequencing of the ANXA11 gene in 180 patients with sporadic ALS. (Elsewhere in the paper, the FALS cohort is noted to include 694 probands). One recurrent mutation, D40G, was found in 3 families and in 1 patient with sporadic ALS; haplotype analysis suggested that the mutation arose on a European background. Four of the 6 mutations identified clustered in the long N terminus, suggesting functional importance. Postmortem tissue available from a patient with the D40G mutation showed classic pathologic features of ALS and large neuronal cytoplasmic ANXA11-immunoreactive inclusions in the spinal cord and certain brain regions, including the motor cortex and occipital lobe. These aggregates formed skein-like, tubular-shaped, filamentous, and complex basket-like structures. These inclusions did not colocalize with TDP43. ANXA11 inclusions were not observed in controls or in patients with other neurodegenerative disorders. Overexpression of mutant ANXA11 in mouse and human cells showed that the R235Q mutant caused increased aggregation, whereas other variants did not. R235Q sequestered wildtype ANXA11 into inclusions, consistent with a dominant-negative effect. Calcyclin binding was inhibited by the D40G, G189E, and R235Q mutations, but was increased by the G38R mutation compared to wildtype. Smith et al. (2017) speculated that loss of calcyclin binding may result in an accumulation of cytoplasmic annexin A11, promoting formation of insoluble aggregates and likely disrupting intracellular protein trafficking.