Recent studies indicate a population-prevalence for USH of 1/6000
]. Children with USH initially have non-syndromic hearing loss (NSHL): RP manifests in the first (USH1) or second (USH2, USH3) decade of life. At least 10% of the hearing-impaired children carry mutations in USH genes, making USH an important differential diagnosis. Molecular genetic testing can confirm or exclude USH at an early time point, even before the onset of visual problems, and may help limiting detailed ophthalmological follow-up in deaf children to those with USH-causing mutations. Moreover, because certain mutations in USH genes cause hearing impairment without retinal degeneration, USH-causing mutations will be unevitably identified in children with apparently NSHL by massively parallel NGS of all known deafness genes – an approach that will become a diagnostic routine within the next few years.
Mutations in the known USH genes account for 72 – 86% of cases
]. The remainder may be due to mutations far outside the coding regions
] or large structural rearrangements
] in these genes that escape detection by genomic DNA amplification and sequencing of the coding exons, and to further genetic heterogeneity. Moreover, USH may be mimicked by clinically overlapping conditions, such as Alström syndrome, or by the co-occurrence of non-syndromic deafness and RP in the same individual
]. Therefore, the awareness of potential differential diagnoses is important when seeking molecular verification of the clinical diagnosis.
Both patients from our family have deafness, RP and cataracts, all symptoms compatible with USH. Linkage analysis excluded all loci for known USH genes, and targeted NGS revealed an ABHD12
nonsense mutation segregating with disease in the family. Truncating ABHD12
mutations have been shown to cause PHARC, a neurodegenerative disease with p
earing loss, a
P, and early c
]. II:1 therefore underwent neurological examination which revealed ataxia – a symptom that may be present in USH1 and USH3 due to the affection of vestibular hair cells. Most patients with PHARC and confirmed ABHD12
mutations had ataxia, and these patients had cerebellar atrophy or peripheral polyneuropathy or both
]. There were no obvious signs of polyneuropathy in patient II:1, and no indication of cerebellar atrophy in the cranial CT scan. However, her balance problems could result from polyneuropathy that remained undetected because detailed investigation of the peripheral nerves had been omitted as long as USH was the clinical diagnosis. II:4 did not complain about balance problems, indicating that ataxia was either very mild or not present. Unfortunately, this patient was not available anymore for detailed clinical follow-up. However, given the homozygous ABHD12
nonsense mutation segregating with the disease, the phenotype in our family can be considered a variant of PHARC.
In retinal photoreceptor cells, the USH protein interactome presumably plays a role in transport, trafficking and synaptic function; in the inner ear, the USH protein interactions are important for hair cell development, maintenance, and for tip link formation and hence mechanotransduction
]. The only known USH3 protein known, clarin-1, has recently been shown to be part of this interactome as well
]. The PHARC protein ABHD12 hydrolyzes 2-arachidonoyl glycerol, an endocannabinoid lipid transmitter that acts on cannabinoid receptors CB1 and CB2. The pathway affected in PHARC is not yet known to be related to the USH protein complex. As can be expected because of the RP component in PHARC, ABHD12
is expressed in the retina
], but no details are available on inner ear expression. Further studies are needed to determine the expression of ABHD12 on the cellular and subcellular level in both sensory systems. The investigation of potential interactions of ABHD12 with the known USH proteins will be crucial to find out if the clinical overlap of PHARC and USH is based on a functional relationship between these proteins.