Variants of LRP2, encoding a multifunctional cell-surface endocytic receptor, associated with hearing loss and retinal dystrophy

Abstract

Hereditary deafness and retinal dystrophy are each genetically heterogenous and clinically variable. Three small unrelated families segregating the combination of deafness and retinal dystrophy were studied by exome sequencing (ES). The proband of Family 1 was found to be compound heterozygous for NM_004525.3: LRP2: c.5005A > G, p.(Asn1669Asp) and c.149C > G, p.(Thr50Ser). In Family 2, two sisters were found to be compound heterozygous for LRP2 variants, p.(Tyr3933Cys) and an experimentally confirmed c.7715 + 3A > T consensus splice-altering variant. In Family 3, the proband is compound heterozygous for a consensus donor splice site variant LRP2: c.8452_8452 + 1del and p.(Cys3150Tyr). In mouse cochlea, Lrp2 is expressed abundantly in the stria vascularis marginal cells demonstrated by smFISH, single-cell and single-nucleus RNAseq, suggesting that a deficiency of LRP2 may compromise the endocochlear potential, which is required for hearing. LRP2 variants have been associated with Donnai-Barrow syndrome and other multisystem pleiotropic phenotypes different from the phenotypes of the four cases reported herein. Our data expand the phenotypic spectrum associated with pathogenic variants in LRP2 warranting their consideration in individuals with a combination of hereditary hearing loss and retinal dystrophy.

Keywords: Donnai-Barrow syndrome; LRP2; RNAseq; deafness; megalin; retinal dystrophy; stria vascularis.

FIGURE 1

Hearing loss and retinal dystrophy associated with LRP2 variants. (A–C) Pedigrees of Families 1, 2, and 3. (D) The 79 coding exons of LRP2 and locations of reported splice variants. (E) Protein domains of LRP2 protein (RefSeq ID NP_004516.2) with reported missense variants (modified from Kantarci et al.). (F) Conservation of human Thr-50, Asn-1669, Cys-3150, and Tyr-3933 residues in LRP2 orthologues (RefSeq ID: Human, NP_004516.2; Chimp, XP_009441920.3; Rhesus, XP_014965780.2; Mouse, NP_001074557.1; Rat, NP_110454.2; Platypus, XP_028927340.1; Zebrafish, NP_001181916.1).