FOXL1

1.4% of PS patients are suspected to have a mutated FOXI1 gene. Some heterozygous variants of FOXI1 are c.77C>T (p.Thr226Ile), c.812G>A(p.Arg271His), c.812G>A(p.Arg271His), which are all rare variants [39]. PS patients have one heterozygous mutation in each of FOXIL and SLC26A4, observed in the SLC26a4+/- and FOXL1+/- double heterozygous mouse model of [39]. 

The FOXL1 gene is responsible for regulating transcription of SLC26A4 on the endolymphatic sac and duct. In a Foxl1-null mouse with EVA and deafness, pendrin was only expressed in the cochlea and vestibular labyrinth. This suggests that it is necessary for pendrin expression in the endolymphatic sac for normal hearing [40].

Mutant mice have a larger endolymphatic duct and sac and vestibular aqueduct. Binary transgenic mice have less enlargement compared to mutant mice.

KCNJ10

3.6% of Pendred Syndrome is caused by a single mutated KCNJ10 gene [1]. The frequency of KCNJ10 mutations are inflated by the inclusion of Chinese and Italian probands, since KCNJ10 variant c.812G>A (p.Arg271His) may be a polymorphism in the Chinese population [39]. 

Mutations in the KCNJ10 gene can also be associated with SLC26A4 mutations. A possible scenario is double heterozygosity, where the Pendred patient carries single mutations in both SLC26A4 and KCNj10. The harmful interaction of mutated SLC26A4 and KCNJ10 results in inner-ear dysfunction. Pathogenic SLC26A4 mutations result in hypofunction or haploinsufficiency, which result in a reduced expression of KCNJ10, causing a reduced supply of K+ to marginal cells in the stria vascularis [26], [48]. The reduced supply of K+ ions results in fluctuating and progressive hearing loss [21], [49], [50]. This suggests that if strial expression could be maintained through controlling endolymph pH levels or limiting oxidative stress through medical therapy, further hearing loss could be prevented [11]. 

Possible mutation combinations include a p.R348C / + in KCNJ10 and c.919-2a→G/+ in SLC26A4, which results in an enlarged vestibular aqueduct. Another case is p.P194H / + in KCNJ10 and p.F335L / + in SLC26A4, which results in an enlarged vestibular aqueduct and Mondini dysplasia [39]. 




Effects of Mutations on the FOXL1 Gene & Frequency of Pendred Patients With FOXL1 Mutation

References: [39], [41]–[47]

Depicts KCNJ10 and Pendrin expression in the cochlea. KCNJ10 is expressed in intermediate cells inside the stria vascularis. Pendrin is expressed in spindle cells, spiral prominence epithelial cells, root cells, and outer sulcus epithelial cells. (Reference: [11])

Effects of Mutations on the KCNJ10 Gene and Frequency of Pendred Patients With KCNJ10 Mutation