RESUMEN
GZF1 was recently reported as a genetic factor associated with Larsen syndrome. Two patients presenting hip dislocation, scoliosis and severe myopia, as well as hearing loss and other abnormal features, were found to carry two novel compounds heterozygous variants in GZF1 (c.397400del, p. Leu133fs; and c.1474del, p. Met492fs) through whole-exome sequencing. The mRNA expression level of L133fs-GZF1 did not significantly differ from that of WT-GZF1. However, no HA-conjugated mutant protein was detected by western blotting, which was also confirmed by immunofluorescence staining. In addition, both mRNA transcription and protein expression levels of M492fs-GZF1 were significantly lower than those of wild type, and HA-tagged M492fs-GZF1 was mainly distributed in the cytoplasm of HEK 293 T cells. These results suggested that the two variants could lead to loss of function of GZF1. Our study was the second to report the association between GZF1 variants and Larsen syndrome. We also provided functional evidence for the pathogenicity of GZF1 variants, which expands the mutation spectrum and offers a basis for functional research on the role of GZF1 in the development of Larsen syndrome.
Asunto(s)
Factores de Transcripción de Tipo Kruppel/genética , Osteocondrodisplasias/genética , Pueblo Asiatico/genética , Femenino , Variación Genética , Humanos , Osteocondrodisplasias/patología , Linaje , Fenotipo , Reacción en Cadena en Tiempo Real de la Polimerasa , Secuenciación del Exoma , Adulto JovenRESUMEN
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.
Asunto(s)
Heterogeneidad Genética , Factores de Transcripción de Tipo Kruppel/genética , Osteocondrodisplasias/genética , Adolescente , Alelos , Niño , Preescolar , Exoma , Femenino , Regulación de la Expresión Génica , Genes Recesivos , Homocigoto , Humanos , Masculino , Mutación , Linaje , Fenotipo , Análisis de Secuencia de ADN , Adulto JovenRESUMEN
Chromosomal microarray analysis is now commonly used in clinical practice to identify copy number variants (CNVs) in the human genome. We report our experience with the use of the 105 K and 180K oligonucleotide microarrays in 215 consecutive patients referred with either autism or autism spectrum disorders (ASD) or developmental delay/learning disability for genetic services at the University of Kansas Medical Center during the past 4 years (2009-2012). Of the 215 patients [140 males and 75 females (male/female ratio=1.87); 65 with ASD and 150 with learning disability], abnormal microarray results were seen in 45 individuals (21%) with a total of 49 CNVs. Of these findings, 32 represented a known diagnostic CNV contributing to the clinical presentation and 17 represented non-diagnostic CNVs (variants of unknown significance). Thirteen patients with ASD had a total of 14 CNVs, 6 CNVs recognized as diagnostic and 8 as non-diagnostic. The most common chromosome involved in the ASD group was chromosome 15. For those with a learning disability, 32 patients had a total of 35 CNVs. Twenty-six of the 35 CNVs were classified as a known diagnostic CNV, usually a deletion (n=20). Nine CNVs were classified as an unknown non-diagnostic CNV, usually a duplication (n=8). For the learning disability subgroup, chromosomes 2 and 22 were most involved. Thirteen out of 65 patients (20%) with ASD had a CNV compared with 32 out of 150 patients (21%) with a learning disability. The frequency of chromosomal microarray abnormalities compared by subject group or gender was not statistically different. A higher percentage of individuals with a learning disability had clinical findings of seizures, dysmorphic features and microcephaly, but not statistically significant. While both groups contained more males than females, a significantly higher percentage of males were present in the ASD group.