Progressive hereditary spastic paraplegia caused by a homozygous KY mutation

Abstract

Twelve individuals of consanguineous Bedouin kindred presented with autosomal recessive progressive spastic paraplegia evident as of age 0-24 months, with spasticity of lower limbs, hyperreflexia, toe walking and equinus deformity. Kyphoscolisois was evident in older patients. Most had atrophy of the lateral aspects of the tongue and few had intellectual disability. Nerve conduction velocity, electromyography and head and spinal cord magnetic resonance imaging were normal in tested subjects. Muscle biopsy showed occasional central nuclei and fiber size variability with small angular fibers. Genome-wide linkage analysis identified a 6.7Mbp disease-associated locus on chromosome 3q21.3-3q22.2 (LOD score 9.02; D3S1290). Whole-exome sequencing identified a single homozygous variant within this locus, c.51_52ins(28); p.(V18fs56*) in KY, segregating in the family as expected and not found in 190 Bedouin controls. High KY transcript levels were demonstrated in muscular organs with lower expression in the CNS. The phenotype is reminiscent of kyphoscoliosis seen in Ky null mice. Two recent studies done independently and parallel to ours describe somewhat similar phenotypes in one and two patients with KY mutations. KY encodes a tranglutaminase-like peptidase, which interacts with muscle cytoskeletal proteins and is part of a Z-band protein complex, suggesting the disease mechanism may resemble myofibrillar myopathy. However, the mixed myopathic-neurologic features caused by human and mouse Ky mutations are difficult to explain by loss of KY sarcomere stabilizing function alone. KY transcription in CNS tissues may imply that it also has a role in neuromotor function, in line with the irregularity of neuromuscular junction in Ky null mutant mice.

Transcriptional upregulation of Bag3, a chaperone-assisted selective autophagy factor, in animal models of KY-deficient hereditary myopathy

“…Disruptive mutations in the Ky gene result in overt muscle pathology in mice ( Bridges et al, 1992 ) and humans ( Hedberg-Oldfors et al, 2016 ; Straussberg et al, 2016 ; Yogev et al, 2017 ). Impaired FLNC turnover is a commonly reported molecular phenotype in mice and humans, which potentially implicates CASA in the pathogenic mechanism.…”

“…Mutations in the KY gene associated with myopathy have been recently reported in human patients ( Hedberg-Oldfors et al, 2016 ; Straussberg et al, 2016 ; Yogev et al, 2017 ). Common pathological hallmarks in mice and humans include muscle atrophy of the soleus and the presence of FLNC aggregates.…”

SCAPER localizes to primary cilia and its mutation affects cilia length, causing Bardet-Biedl syndrome

“…Genome-wide linkage analysis was performed using Illumina Omni Express Beadchip with >700 K SNP loci per sample (Illumina, San Diego, CA, USA), as previously described [13]. Homozygosity mapping analysis was carried out using Homozygosity-Mapper [14], and Multipoint Logarithm of Odds (LOD) score for the pedigree P1 ( Fig.…”

Combined CNV, haplotyping and whole exome sequencing enable identification of two distinct novel EYS mutations causing RP in a single inbred tribe

“…Enriched libraries were sequenced using hiSeq 2,500 (Illumina Inc., San Diego, CA) at an average coverage depth of ~70X–100X, ensuring that >96.7% of the regions of interest have enough coverage (>10X) for variation detection. WES data were analyzed through QIAGEN®’s Ingenuity Variant Analysis™ software (http://www.qiagen.cm/ingenuity, Qiagen, Inc., Redwood City, CA), using a filtering cascade to exclude variants, as previously described (Yogev et al, ). Briefly, we excluded common variants observed with an allele frequency ≥0.5% of the genomes in the 1,000 genomes project, NHLBI ESP exomes (All), exome aggregation consortium (ExAC) and genome aggregation database (gnomAD) data sets (Lek et al, ) or the allele frequency community (http://www.allelefrequencycommunity.org/), and variants which appeared in a homozygous state in our in‐house whole‐exome sequencing database of 200 Bedouin control samples.…”

“…The Bedouin community residing in southern Israel has high rates of consanguinity and fecundity culminating in an array of inherited diseases, arising from homozygosity of founder mutations (Markus, Alshafee, & Birk, ; Na'amnih et al, ; Sharon et al, ). Our laboratory's studies of inbred communities have been conducive to the discovery of disease‐causing mutations underlying numerous inherited syndromes affecting different biologic systems, including specific progress in identifying heritable eye diseases, and more specifically––inherited retinal diseases (IRDs) (Gradstein et al, ; Mordechai et al, ; Perez et al, ; Yogev et al, ). To date, as many as 260 genes have been identified as causing IRDs, including Bardet–Biedl syndrome (BBS), chorioretinal atrophy, cone‐rod dystrophy, Leber congenital amaurosis, Usher syndrome, and most commonly retinitis pigmentosa (RP) (Farrar et al, ; SP Daiger, Greenberg, & Christoffels, ).…”