New clinical and molecular evidence linking mutations in ARSG to Usher syndrome type IV (USH4)


Source: WileyOnline Library

Virginie G. Peter,Mathieu Quinodoz,Silvia Sadio,Sebastian Held,Márcia Rodrigues,Marta Soares,Ana Berta Sousa,Luisa Coutinho Santos,Markus Damme,Carlo Rivolta


In murine and canine animal models, mutations in the Arylsulfatase G gene (ARSG) cause a particular lysosomal storage disorder characterized by neurological phenotypes. Recently, two variants in the same gene were found to be associated with an atypical form of Usher syndrome in humans, leading to visual and auditory impairment without the involvement of the central nervous system. In this study, we identified three novel pathogenic variants in ARSG, which segregated recessively with the disease in two families from Portugal. The probands were affected with retinitis pigmentosa and sensorineural hearing loss, generally with an onset of symptoms in their fourth decade of life. Functional experiments showed that these pathogenic variants abolish the sulfatase activity of the Arylsulfatase G enzyme and impede the appropriate lysosomal localization of the protein product, which appears to be retained in the endoplasmic reticulum. Our data enable to definitely confirm that different biallelic variants in ARSG cause a specific deaf-blindness syndrome, by abolishing the activity of the enzyme it encodes.


Source: OMIM

A number sign (#) is used with this entry because of evidence that Usher syndrome type IV (USH4) is caused by homozygous or compound heterozygous mutation in the ARSG gene (610008) on chromosome 17q24.


An atypical form of Usher syndrome, here designated type IV (USH4), is an autosomal recessive disorder characterized by late onset of retinitis pigmentosa and usually late-onset of progressive sensorineural hearing loss without vestibular involvement (summary by Khateb et al., 2018). 

Clinical Features

Khateb et al. (2018) described 5 patients from 3 Yemenite Jewish families (MOL0120, MOL0737, and TB55) with an atypical form of Usher syndrome. All affected individuals presented with a distinctive late-onset retinal phenotype, including ring-shaped retinal atrophy delimiting the vascular arcades temporally and extending beyond the optic nerve nasally, with relative preservation of the mid- and far-periphery. Over time, pigment migration occurred within the atrophic areas, forming bone-spicule-like pigmentary changes as well as pigment clumps, and the central macula also became involved. Electroretinographic testing showed severely decreased rod and mixed cone-rod responses. Electrooculography testing, which was performed on 3 patients, showed that the Arden ratio was reduced, suggesting injury to the retinal pigment epithelium, either as a primary event or secondary to photoreceptor degeneration. None of the patients reported significant abnormalities of the vestibular system. Affected sibs from 2 families presented with progressive moderate to severe sensorineural hearing loss at a relatively late age, usually after age 40; hearing loss in the single patient from the third family began in childhood and deteriorated around the age of 18. 

Abad-Morales et al. (2020) reported a 44-year-old Spanish woman who presented at 40 years of age with progressive nyctalopia and a history of hearing loss since infancy. Ophthalmologic examination showed a pericentral retinal pigment epithelium abnormality extending beyond the optic nerve with mid-peripheral spicule-like abnormalities. Fundus autofluorescence imaging showed a hypoautofluorescent area at the level of the vascular arcades and another hypoautofluorescent area surrounding the macula. In the ensuing 4 years, the area of retinal degeneration did not change, but autofluorescence imaging showed that the retinal pigment disturbances became more marked. 

Peter et al. (2021) reported 2 Portuguese women with Usher syndrome type IV. Individual 1 (LL64) had decreased progressive visual acuity beginning at 45 years of age. At approximately 60 years of age, she developed nyctalopia, peripheral vision loss, photopsia, and dyschromatopsia. Fundus examination at age 72 years showed areas of chorioretinal atrophy and pigmentary migration forming spicule-like changes in the mid-periphery. Optical coherence tomography (OCT) showed conserved retinal layers at the fovea with peripheral atrophy and loss of the photoreceptor layer. Fundus autofluorescence imaging showed hypofluorescence at the level of the vascular arcades. She also developed progressive sensorineural hearing loss starting at 40 years of age. Individual 2 (LL197) was diagnosed with retinitis pigmentosa after the onset of nyctalopia at 35 years of age. At age 59 years she had significantly decreased vision and could only detect hand movements. Fundus examination showed bilateral pale optic discs and vascular attenuation. There were pigmentary deposits along the arcades of the macula. Fundus autofluorescence imaging showed hypofluorescence at the level of the vascular arcades and a fluorescent parafoveal ring. She also developed sensorineural hearing loss at 50 years of age. Neither patient had vestibular symptoms. 

Fowler et al. (2021) reported a 60-year-old patient with a 20-year history of progressive sensorineural hearing loss and a 10-year history of progressive peripheral vision loss and pigmentary retinopathy. Fundus examination showed ring-shaped retinal hyperpigmentation around the macula and extending to the arcades, and fundus autofluorescence imaging showed a 6-zone pattern of autofluorescence. OCT showed hyporeflective cystoid spaces predominantly in the ganglion cell layer, and widefield OCT angiography revealed signs of atrophy at the level of the choriocapillaris. 


By homozygosity mapping followed by whole-genome and whole-exome sequencing in 3 Yemenite Jewish families segregating an atypical form of Usher syndrome, Khateb et al. (2018) identified a single shared homozygous 66- to 69.4-Mb region on chromosome 17. 

Molecular Genetics

In 5 affected members of 3 consanguineous Yemenite Jewish families with an atypical form of Usher syndrome (618144), Khateb et al. (2018) identified homozygosity for a missense mutation in the ARSG gene (D45Y; 610008.0001). The mutation, which was confirmed by Sanger sequencing, segregated with the disorder in the families. All haplotypes surrounding the variant were identical, indicating that it is a founder mutation. The mutation was found in heterozygous state in 1 of 101 Yemenite Jewish controls, corresponding to a minor allele frequency of 0.005, and was not found in the gnomAD database. 

Abad-Morales et al. (2020) identified a homozygous mutation in the ARSG gene (D44N; 610008.0002) in a 44-year-old Spanish woman with USH4. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. 

Peter et al. (2021) reported 2 Portuguese patients with USH4 and mutations in the ARSG gene. Individual 1 (LL64) had a homozygous mutation (610008.0003) and individual 2 (ILL197) had compound heterozygous mutations (610008.0004-610008.0005). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. All 3 mutations were shown to abolish acid sulfatase activity to lead to protein mislocalization to the endoplasmic reticulum. 

In a 60-year-old Persian man with USH4, Fowler et al. (2021) identified a homozygous mutation in the ARSG gene (R424C; 610008.0006). 


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