Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy

Abstract

Objective: To improve the genetic diagnosis of dominant optic atrophy (DOA), the most frequently inherited optic nerve disease, and infer genotype-phenotype correlations.

Methods: Exonic sequences of 22 genes were screened by new-generation sequencing in patients with DOA who were investigated for ophthalmology, neurology, and brain MRI.

Results: We identified 7 and 8 new heterozygous pathogenic variants in SPG7 and AFG3L2. Both genes encode for mitochondrial matricial AAA (m-AAA) proteases, initially involved in recessive hereditary spastic paraplegia type 7 (HSP7) and dominant spinocerebellar ataxia 28 (SCA28), respectively. Notably, variants in AFG3L2 that result in DOA are located in different domains to those reported in SCA28, which likely explains the lack of clinical overlap between these 2 phenotypic manifestations. In comparison, the SPG7 variants identified in DOA are interspersed among those responsible for HSP7 in which optic neuropathy has previously been reported.

Conclusions: Our results position SPG7 and AFG3L2 as candidate genes to be screened in DOA and indicate that regulation of mitochondrial protein homeostasis and maturation by m-AAA proteases are crucial for the maintenance of optic nerve physiology.

Figure 1. SPG7 and AFG3L2 pedigrees

Description of the pedigrees with SPG7 (top) and AFG3L2 (middle and bottom) mutations and their segregation among the DOA families. DOA = dominant optic atrophy.

Figure 2. Ophthalmologic exploration of SPG7 and an AFG3L2 affected individuals

Left: Eye fundus pictures of individuals with SPG7 (A, family 5, II.1 and family 6 II.1) and individuals with AFG3L2 (B, family 9, III:2 and family 12, II.1) revealing the temporal pallor of the optic discs in both REs and LEs. Right: RNFL by optic coherence tomography in individuals, disclosing the mild reduction of RNFL thickness in the individuals with SPG7 (A) and the severe one in the individuals with AFG3L2 (B). The green area defines the 5th to 95th, the yellow area the 1st to 5th, and the red area below the 1st percentiles. INF = inferior quadrants; LE = left eye; NAS = nasal; RE = right eye; RNFL = retinal nerve fiber layer assessment; SUP = superior; TEMP = temporal.

Figure 3. Structural representation of SPG7 and AFG3L2 amino acid changes related to mutations in individuals with DOA, HSP7, and SCA28/SPAX5

(A): Structure and domains of the SPG7 protein with the amino acid changes associated with DOA (top) and HSP7 (bottom); red, mutations identified in this study; purple, a DOA mutation previously reported; and black: HSP7 published mutations. (B): Structure and domains of the AFG3L2 protein with the amino acid changes associated with DOA (top) and to other diseases (bottom); red, mutations identified in this study; purple, a previously reported DOA mutation; black, published mutations responsible for SCA28; blue, published mutations responsible for recessive spastic ataxia SPAX5; in green, myoclonus and pyramidal signs; and in orange, microcephaly, early onset seizures, spasticity, and basal ganglia atrophy. DOA = dominant optic atrophy; SCA28 = spinocerebellar ataxia; SPAX5 = spastic ataxia-neuropathy syndrome.