Recessive mutations in SLC38A8 cause foveal hypoplasia and optic nerve misrouting without albinism

Abstract

Foveal hypoplasia and optic nerve misrouting are developmental defects of the visual pathway and only co-occur in connection with albinism; to date, they have only been associated with defects in the melanin-biosynthesis pathway. Here, we report that these defects can occur independently of albinism in people with recessive mutations in the putative glutamine transporter gene SLC38A8. Nine different mutations were identified in seven Asian and European families. Using morpholino-mediated ablation of Slc38a8 in medaka fish, we confirmed that pigmentation is unaffected by loss of SLC38A8. Furthermore, by undertaking an association study with SNPs at the SLC38A8 locus, we showed that common variants within this gene modestly affect foveal thickness in the general population. This study reveals a melanin-independent component underpinning the development of the visual pathway that requires a functional role for SLC38A8.

Figure 1

Foveal Hypoplasia and Chiasmal Misrouting Are Present in Individuals with Recessive SLC38A8 Mutations (A and B) Fundus photographs of the left (A) and right (B) eyes of individual IV:1 from family F5 at 12 years of age show retinal vessels within the normally avascular macula region, signifying foveal hypoplasia. (C) A normal control fundus is included for comparison. Note that the fundus pigmentation in (A)–(C) is normal and represents natural variation. An optical-coherence-tomography scan of the left eye of the same child at the age of 11 years confirmed foveal hypoplasia. (D) A fundus image showing the position of the scan (green arrow) spans the presumptive foveal region (white circle). (E) Scan results show normal retinal morphology but the absence of a foveal pit. (F) Flash VEP results of individual IV:1 from family F1 show contralateral asymmetry of VEP, demonstrating chiasmal misrouting. The arrow shows the N2 peak, which is similar to that seen in albinos. Abbreviations are as follows: OD, right eye; and OS, left eye. Note that the time on the x axis begins at −15 ms.

Figure 2

Pedigrees of Families Reported in This Study and Mutation Segregation Data Affected individuals are shaded black. Detailed descriptions of members of F1, F2, F3, and F6 have been reported previously. The husband of the affected individual in F3 has oculocutaneous albinism (gray shading). In family F6, the members with a question mark have not undergone a full clinical examination, but the fact that they have esotropia, poor vision, and nystagmus suggests that they have the same condition. The mutation genotypes for all tested family members are shown below each individual—M represents the mutant allele, and + represents the wild-type allele.

Figure 3

Mutations in SLC38A8 Cause Foveal Hypoplasia and Optic-Nerve-Decussation Defects (A) A schematic representation of the SLC38A8 genomic structure and transcript shows the location and sequence traces of eight mutations identified in this study. (B) A schematic diagram of SLC38A8 shows the location of the alterations within the protein domains. The compound-heterozygous changes are in parentheses.

Figure 4

Morpholino Knockdown of Slc38a8 in Medaka Fish Results in Microphthalmia, Coloboma, and Lens Defects, but No Skin- or Ocular-Pigmentation Abnormalities (A) Bright-field stereomicroscope images show lateral views of representative fish for the controls and Mo-5′UTR-slc38a8 c3+c6 and Mo-5′UTR-Slc38a8 c3+c6/Mo-p53 mutants. The red bracket highlights the reduced eye size in morphants, and the arrows highlight displaced lenses. Ocular pigmentation identical to that of the controls can clearly be seen in the mutant fish. (B) The frequency of each phenotype observed in the medaka fish is given as a percentage of 300.