Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene

Abstract

Sequencing exomes/genomes have been successful for identifying recessive genes; however, discovery of dominant genes including deafness genes (DFNA) remains challenging. We report a new DFNA gene, ATP11A, in a Newfoundland family with a variable form of bilateral sensorineural hearing loss (SNHL). Genome-wide SNP genotyping linked SNHL to DFNA33 (LOD = 4.77), a locus on 13q34 previously mapped in a German family with variable SNHL. Whole-genome sequencing identified 51 unremarkable positional variants on 13q34. Continuous clinical ascertainment identified several key recombination events and reduced the disease interval to 769 kb, excluding all but one variant. ATP11A (NC_000013.11: chr13:113534963G>A) is a novel variant predicted to be a cryptic donor splice site. RNA studies verified in silico predictions, revealing the retention of 153 bp of intron in the 3′ UTR of several ATP11A isoforms. Two unresolved families from Israel were subsequently identified with a similar, variable form of SNHL and a novel duplication (NM_032189.3:c.3322_3327+2dupGTCCAGGT) in exon 28 of ATP11A extended exon 28 by 8 bp, leading to a frameshift and premature stop codon (p.Asn1110Valfs43Ter). ATP11A is a type of P4-ATPase that transports (flip) phospholipids from the outer to inner leaflet of cell membranes to maintain asymmetry. Haploinsufficiency of ATP11A, the phospholipid flippase that specially transports phosphatidylserine (PS) and phosphatidylethanolamine (PE), could leave cells with PS/PE at the extracellular side vulnerable to phagocytic degradation. Given that surface PS can be pharmaceutically targeted, hearing loss due to ATP11A could potentially be treated. It is also likely that ATP11A is the gene underlying DFNA33.

TMEM30A is essential for hair cell polarity maintenance in postnatal mouse cochlea

“…Our study highlighted the pivotal role of TMEM30A in maintaining the integrity and functional maturation of hair cells during postnatal development in mice and uncovered the potential mechanisms of P4-ATPase mutation-related genetic hearing loss [ 4 , 6 ]. By observing the spatial and temporal expression of P4-ATPase subtypes and the β-subunit TMEM30A in the mouse cochlea, we demonstrated the expression differences of these flippases and defined the temporal pattern of TMEM30A expression in the cochlea.…”

“…Over 250 genes are related to syndromic and nonsyndromic hearing loss [ 3 ]. Recently, ATP11A was reported as the gene related to DFNA33, a form of bilateral sensorineural hearing loss found in three Caucasian families [ 4 , 5 ]. ATP8A2 is also required for normal visual and auditory function, while its mutation impedes the survival of photoreceptor and spiral ganglion neurons [ 6 ].…”

A systematic review of the monogenic causes of Non‐Syndromic Hearing Loss (NSHL) and discussion of Current Diagnosis and Treatment options

“…[168], Sanger seq. [233] in the specification of neuroblasts, sensory epithelium; induction of otic placode, and otic vesicle morphogenesis. 250 BMPs (Bone Morphogenetic Proteins) are a group of 20 members that make the largest subfamily of the TGF β superfamily 251 ; regulates the fate map of supporting cells from the prosensory domain and specifies the non-sensory cells in the cochlea.…”

Strategies for activity analysis of single nucleotide polymorphisms associated with human diseases

“…22,23 In addition, it can also cause exon skipping and intron retention by disturbing exon splicing. [24][25][26][27] In the non-coding regions, some SNP sites located in the promoter region affect the activity of the promoter by altering the affinity of transcription factors, thereby resulting in the increased expression or decreased expression of genes. [28][29][30] In addition, SNP sites located in enhancer or silencer regions can enhance or silence the expression of target genes through interactions with distal regulatory elements such as promoters.…”

“…In the protein‐coding region, a few functional SNP sites can induce abnormal protein translation by directly changing the amino acid sequence 22,23 . In addition, it can also cause exon skipping and intron retention by disturbing exon splicing 24–27 . In the non‐coding regions, some SNP sites located in the promoter region affect the activity of the promoter by altering the affinity of transcription factors, thereby resulting in the increased expression or decreased expression of genes 28–30 .…”