GZF1 Mutations Expand the Genetic Heterogeneity of Larsen Syndrome

Abstract

Larsen syndrome is characterized by the dislocation of large joints and other less consistent clinical findings. Heterozygous FLNB mutations account for the majority of Larsen syndrome cases, but biallelic mutations in CHST3 and B4GALT7 have been more recently described, thus confirming the existence of recessive forms of the disease. In a multiplex consanguineous Saudi family affected by severe and recurrent large joint dislocation and severe myopia, we identified a homozygous truncating variant in GZF1 through a combined autozygome and exome approach. Independently, the same approach identified a second homozygous truncating GZF1 variant in another multiplex consanguineous family affected by severe myopia, retinal detachment, and milder skeletal involvement. GZF1 encodes GDNF-inducible zinc finger protein 1, a transcription factor of unknown developmental function, which we found to be expressed in the eyes and limbs of developing mice. Global transcriptional profiling of cells from affected individuals revealed a shared pattern of gene dysregulation and significant enrichment of genes encoding matrix proteins, including P3H2, which hints at a potential disease mechanism. Our results suggest that GZF1 mutations cause a phenotype of severe myopia and significant articular involvement not previously described in Larsen syndrome.

Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome

“…Thalidomide embryopathies thus represent a case in which animal studies fall short, and it is likely that the clinical features of IMiD efficacy as well as adverse effects, are a result of induced degradation of multiple C 2 H 2 zinc finger transcription factors. For example, we see some degree of degradation for GZF1, another C 2 H 2 transcription factor, while GZF1 is unlikely to cause the defining birth defects of thalidomide, mutations in GZF1 have been associated with joint laxity and short stature, which are both also found in thalidomide-affected children ( Patel et al, 2017 ). We also note that CRBN expression levels influence the efficacy of IMiDs in inducing protein degradation, and it is conceivable that these contribute to a certain degree of tissue selectivity of IMiD effects, which for example, could increase the therapeutic index in MM as hematopoietic lineages tend to have high levels of CRBN.…”

Dynamic enhancers control skeletal muscle identity and reprogramming

“…Multiple proteins associated with muscle atrophy or hypertrophy were inferred, including STAT5A, FOXO4, MAFB, and ATF4. In addition, the GDNF inducible zinc finger protein 1 (GZF1) and heat shock transcription factor 4 (HSF4) repressors and NFYB were identified, which have little known function [65,66]. Some of these putative transcriptional effectors of exercise, including MEF2, SIX, and TEAD, were also identified in a motif-based analysis of differentially methylated DNA positions in muscle from humans subjected to chronic training [67].…”

Genetic testing for the diagnosis and classification of joint hypermobility: a case report of 15 patients

“…The proband 2 in our study mainly presented with dislocation of hip and contractures of shoulders and elbow joints, which can't get an accurate diagnosis according to the clinical symptoms. Proband 1, proband 3 and proband 4 were diagnosed with suspected JHS/JH-related disorders, the genetic results revelated mutations in COL11A1, NALCN and GALNS, which can lead to Stickler syndrome, CLIFAHDD syndrome, Mucopolysaccharidosis IVA, respectively [16,[23][24][25][26]. The genetic results corrected the first clinical diagnosis.…”