Optic Atrophy 5

A number sign (#) is used with this entry because of evidence that optic atrophy-5 (OPA5) is caused by heterozygous mutation in the DNM1L gene (603850) on chromosome 12p11.

Description

OPA5 is an autosomal dominant form of nonsyndromic optic atrophy, manifest as slowly progressive visual loss with variable onset from the first to third decades. Additional ocular abnormalities may include central scotoma and color vision defects. The pathogenesis is related to defective mitochondrial fission (summary by Gerber et al., 2017).

For a discussion of genetic heterogeneity of optic atrophy, see OPA1 (165500).

Clinical Features

Barbet et al. (2005) described 2 unrelated 3-generation French families (families A and B) with autosomal dominant optic atrophy. Although the age of onset was in the first decade in one family and in the third decade in the other, the phenotype was similar in both families and resembled that of patients with mutations in the OPA1 gene. All of the examined patients had optic nerve pallor. Visual acuity decreased slowly, perhaps related to a central scotoma. Color vision was moderately impaired, varying from normal to blue-yellow dyschromatopsia; after several years of evolution, patients showed a severe dyschromatopsia without axis. Electroretinogram recordings were normal, but visual evoked potential recordings were moderately altered in the early stages and severely impaired in the later stages.

Gerber et al. (2017) reported a large multigenerational French family (family 1) in which 8 individuals, 5 of whom were still living, had nonsyndromic optic atrophy. Four patients from 2 generations were examined; they were 10, 14, 40, and 49 years of age. The youngest patient was asymptomatic, the 14 year-old had moderate photophobia, and the older patients had decreased visual acuity beginning at 35 and 45 years, respectively. However, all had abnormalities on detailed eye studies, including narrowing of the visual fields. Three patients had central scotoma, and 2 had moderate color vision defects. All had temporal pallor of the optic discs, and a reduction of retinal nerve fiber layer thickness around the optic nerve head. Visual evoked potentials were moderately to severely impaired. One individual had moderate hearing loss, but otherwise, none had additional neurologic findings. Gerber et al. (2017) reported follow-up of the families reported by Barbet et al. (2005): family A was referred to as family 2, and family B was referred to as family 3. The phenotype of these patients had not changed significantly from the original report.

Inheritance

The transmission pattern of OPA5 in the families reported by Gerber et al. (2017) was consistent with autosomal dominant inheritance.

Molecular Genetics

In affected members from 3 unrelated French families with OPA5, Gerber et al. (2017) identified 2 different heterozygous missense mutations in the DNM1L gene (E2A, 603850.0009 and A192E, 603850.0010). The mutations in the first 2 families were found by exome sequencing and confirmed by Sanger sequencing; the mutation in the third family was found by direct sequencing of the DNM1L gene. The mutations segregated with the disorder in all 3 families. Patient fibroblasts showed that the mutant proteins were expressed, were able to dimerize with wildtype DNM1L, and formed aggregates in both the cytoplasm and on the mitochondrial network. Mitochondria in mutant cells showed a highly elongated, hyperfilamentous, and tubulated network with a decrease in the number of mitochondrial extremities, suggesting an impairment of mitochondrial fission. In addition, DNM1L clusters were not associated with mitochondrial constriction sites in mutant fibroblasts. The findings were consistent with a dominant-negative effect. There were no structural differences of the peroxisomal network, nor alteration of the respiratory machinery. Heterozygous knockdown of the Dnm1l gene in mice (Dnm1l +/-) resulted in the elongation of the mitochondrial network of retinal ganglion cells, but no axonal degeneration in the optic nerve. Two of the families had previously been reported by Barbet et al. (2005). Gerber et al. (2017) noted that OPA1, which has a similar phenotype, results from impaired mitochondrial fusion, suggesting that retinal ganglion cells are particularly sensitive to mitochondrial membrane dynamics.

History

Barbet et al. (2005) performed genomewide mapping in a 3-generation French family with autosomal dominant OPA and found that all 8 affected individuals shared a common haplotype on chromosome 22q12.1-q13.1. Obligatory recombination events defined a 10.4-cM critical interval between D22S1148 and D22S283. Haplotype analysis of a second 3-generation French family with autosomal dominant optic atrophy also showed linkage to the region of interest on chromosome 22q. Analyzing the 2 families together, Barbet et al. (2005) obtained a maximum lod score of 3.75 (theta = 0.0) at D22S1176, with penetrance set at 100% (all 12 individuals with the disease haplotype were affected with optic atrophy). Screening of 3 candidate genes, OSBP2 (606729), HSC20 (608142), and HSPC051, in these families failed to identify any disease-causing alterations.

In the families reported by Barbet et al. (2005), Gerber et al. (2017) identified mutations in the DNM1L gene on chromosome 12p11, thus denying the existence of a 'OPA5' locus on chromosome 22q and redefining it on 12p11.