A conserved function of Pkhd1l1, a mammalian hair cell stereociliary coat protein, in regulating hearing in zebrafish

Makrogkikas, Stylianos; Cheng, Ruey‐Kuang; Lu, Hao; Roy, Sudipto

doi:10.1080/01677063.2023.2187792

Cited by 3 publications

(8 citation statements)

References 23 publications

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“…Mice lacking Pkdh1l1 displayed elevated auditory brainstem responses (ABR) and distortion product otoacoustic emissions (DPOAE) thresholds in response to pure tone stimuli in a progressive fashion (Wu et al 2019), and lacked the stereocilia coat. More recent data from zebrafish (Danio rerio, Dr) with a double knockout of pkhd1l1a and pkhd1l1b (orthologs of human (Hs) PKHD1L1) show significant deficits in auditory startle responses at the larval stage, consistent with an early-onset auditory phenotype in zebrafish (Makrogkikas et al 2023). Based on these findings in animal models, we sought to determine whether variants in PKHD1L1 cause hearing loss in humans.…”

Section: Introductionmentioning

confidence: 83%

“…Furthermore, it is unknown whether PKHD1L1 is the only component of the stereocilia coat. Recently, pkhd1l1 was shown to play a critical role in regulating hearing in zebrafish (Makrogkikas et al 2023). pkhdl1l has a ubiquitous expression pattern and is sustained for most of embryonic development (Makrogkikas et al 2023).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, pkhd1l1 was shown to play a critical role in regulating hearing in zebrafish (Makrogkikas et al 2023). pkhdl1l has a ubiquitous expression pattern and is sustained for most of embryonic development (Makrogkikas et al 2023). Through depletion of the two paralogous genes ( pkhd1l1a and pkhd1l1b ), double mutant zebrafish exhibited significant hearing loss from the larval stage (6 days post fertilization) which differs compared to progressive hearing loss in the mouse (Wu et al 2019).…”

Section: Discussionmentioning

confidence: 99%

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PKHD1L1, A Gene Involved in the Stereocilia Coat, Causes Autosomal Recessive Nonsyndromic Hearing Loss

Redfield,

De-la-Torre,

Zamani

et al. 2023

Preprint

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Identification of genes associated with nonsyndromic hearing loss is a crucial endeavor, given the substantial number of individuals who remain without a diagnosis after even the most advanced genetic testing.PKHD1L1was established as necessary for the formation of the cochlear hair-cell stereociliary coat and causes hearing loss in mice and zebrafish when mutated. We sought to determine if biallelic variants inPKHD1L1also cause hearing loss in humans.Exome sequencing was performed on DNA of three families segregating autosomal recessive moderate to severe nonsyndromic sensorineural hearing loss. Compound heterozygous missense p.[(Gly129Ser)];p.[(Gly1314Val)], homozygous missense p.(His2479Gln) and nonsense p.(Arg3381Ter) variants were identified inPKHD1L1that were predicted to be damaging usingin silicopathogenicity prediction methods.In vitrofunctional analysis of two missense variants was performed using purified recombinant PKHD1L1 protein fragments. We then evaluated protein thermodynamic stability with and without the missense variants found in one of the families.In vitrofunctional assessment indicated that both engineered PKHD1L1 mutant p.(Gly129Ser) and p.(Gly1314Val) constructs significantly reduced the folding and structural stabilities of the expressed protein fragments, providing further evidence to support pathogenicity of these variants.In silicomolecular modelling using AlphaFold2 and protein sequence alignment analysis were carried out to further explore potential variant effects on protein folding and stability and exposed key structural features that might suggest PKHD1L1 protein destabilization.Multiple lines of evidence collectively associatePKHD1L1with nonsyndromic mild-moderate to severe sensorineural hearing loss.PKHD1L1testing in individuals with mild-moderate hearing loss may identify further affected families.

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Section: Introductionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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PKHD1L1, A Gene Involved in the Stereocilia Coat, Causes Autosomal Recessive Nonsyndromic Hearing Loss

Redfield,

De-la-Torre,

Zamani

et al. 2023

Preprint

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“…PKHD1L1-deficient mice showed no major morphological disruption to hair bundles at the onset of hearing; however, after initially exhibiting near-normal ABR and DPOAE thresholds, develop progressive hearing loss later in life (Wu et al, 2019). Similarly, auditory disruption has also been described in zebrafish deficient in PKHD1L1 (Makrogkikas et al, 2023). Double knockout of pkhd1l1 zebrafish paralogs, pkhd1l1α and pkhd1l1β, reduces auditory-evoked startle responses in zebrafish at larvae stages, indicative of an early-onset hearing loss.…”

Section: Introductionmentioning

confidence: 94%

“…Similarly, knockout of pkhd1l1 zebrafish paralogs, pkhd1l1α and pkhd1l1β, reduces auditory-evoked startle responses in zebrafish at larval stages, indicative of an early-onset hearing loss. (Makrogkikas et al, 2023). In humans, we recently reported biallelic variants of PKHD1L1 in four unrelated families with congenital non-syndromic sensorineural hearing loss (Redfield et al, 2024).…”

Section: Introductionmentioning

confidence: 99%

PKHD1L1 is required for stereocilia bundle maintenance, durable hearing function and resilience to noise exposure

Strelkova,

Osgood,

Tian

et al. 2024

Preprint

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Sensory hair cells of the cochlea are essential for hearing, relying on the mechanosensitive stereocilia bundle at their apical pole for their function. Polycystic Kidney and Hepatic Disease 1-Like 1 (PKHD1L1) is a stereocilia protein required for normal hearing in mice, and for the formation of the transient stereocilia surface coat, expressed during early postnatal development. While the function of the stereocilia coat remains unclear, growing evidence supports PKHD1L1 as a human deafness gene. In this study we carry out in depth characterization of PKHD1L1 expression in mice during development and adulthood, analyze hair-cell bundle morphology and hearing function in aging PKHD1L1-defficient mouse lines, and assess their susceptibility to noise damage. Our findings reveal that PKHD1L1-deficient mice display no disruption to bundle cohesion or tectorial membrane attachment-crown formation during development. However, starting from 6 weeks of age, PKHD1L1-defficient mice display missing stereocilia and disruptions to bundle coherence. Both conditional and constitutive PKHD1L1 knock-out mice develop high-frequency hearing loss progressing to lower frequencies with age. Furthermore, PKHD1L1-deficient mice are susceptible to permanent hearing loss following low-level acoustic overexposure, which typically induces only temporary shifts in hearing thresholds. These results suggest a role for PKHD1L1 in establishing robust sensory hair bundles during development, necessary for maintaining bundle cohesion and function in response to acoustic trauma and aging.

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PKHD1L1, a gene involved in the stereocilia coat, causes autosomal recessive nonsyndromic hearing loss

Redfield,

De-la-Torre,

Zamani

et al. 2024

Hum. Genet.

View full text Add to dashboard Cite

Identification of genes associated with nonsyndromic hearing loss is a crucial endeavor given the substantial number of individuals who remain without a diagnosis after even the most advanced genetic testing. PKHD1L1 was established as necessary for the formation of the cochlear hair-cell stereociliary coat and causes hearing loss in mice and zebrafish when mutated. We sought to determine if biallelic variants in PKHD1L1 also cause hearing loss in humans. Exome sequencing was performed on DNA of four families segregating autosomal recessive nonsyndromic sensorineural hearing loss. Compound heterozygous p.[(Gly129Ser)];p.[(Gly1314Val)] and p.[(Gly605Arg)];p[(Leu2818TyrfsTer5)], homozygous missense p.(His2479Gln) and nonsense p.(Arg3381Ter) variants were identified in PKHD1L1 that were predicted to be damaging using in silico pathogenicity prediction methods. In vitro functional analysis of two missense variants was performed using purified recombinant PKHD1L1 protein fragments. We then evaluated protein thermodynamic stability with and without the missense variants found in one of the families and performed a minigene splicing assay for another variant. In silico molecular modeling using AlphaFold2 and protein sequence alignment analysis were carried out to further explore potential variant effects on structure. In vitro functional assessment indicated that both engineered PKHD1L1 p.(Gly129Ser) and p.(Gly1314Val) mutant constructs significantly reduced the folding and structural stabilities of the expressed protein fragments, providing further evidence to support pathogenicity of these variants. Minigene assay of the c.1813G>A p.(Gly605Arg) variant, located at the boundary of exon 17, revealed exon skipping leading to an in-frame deletion of 48 amino acids. In silico molecular modeling exposed key structural features that might suggest PKHD1L1 protein destabilization. Multiple lines of evidence collectively associate PKHD1L1 with nonsyndromic mild–moderate to severe sensorineural hearing loss. PKHD1L1 testing in individuals with mild–moderate hearing loss may identify further affected families.

show abstract

A conserved function of Pkhd1l1, a mammalian hair cell stereociliary coat protein, in regulating hearing in zebrafish

Cited by 3 publications

References 23 publications

PKHD1L1, A Gene Involved in the Stereocilia Coat, Causes Autosomal Recessive Nonsyndromic Hearing Loss

PKHD1L1, A Gene Involved in the Stereocilia Coat, Causes Autosomal Recessive Nonsyndromic Hearing Loss

PKHD1L1 is required for stereocilia bundle maintenance, durable hearing function and resilience to noise exposure

PKHD1L1, a gene involved in the stereocilia coat, causes autosomal recessive nonsyndromic hearing loss

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