Loss of function mutation in glutamic pyruvate transaminase 2 (GPT2) causes developmental encephalopathy

Intellectual disability is genetically heterogeneous, and it is likely that many of the responsible genes have not yet been identified. We describe three siblings with isolated, severe developmental encephalopathy. After extensive uninformative genetic and metabolic testing, whole exome sequencing identified a homozygous novel variant in glutamic pyruvate transaminase 2 (GPT2) or alanine transaminase 2 (ALT2), c.459 C>G p.Ser153Arg that segregated with developmental encephalopathy in the family. This variant was predicted to be damaging by all in silico prediction algorithms. GPT2 is the gene encoding ALT2 which is responsible for the reversible transamination of alanine and 2-oxoglutarate to form pyruvate and glutamate. GPT2 is expressed in brain and is in the pathway to generate glutamate, an excitatory neurotransmitter. Functional assays of recombinant wild-type and mutant ALT2 proteins demonstrated the p.Ser153Arg mutation resulted in a severe loss of enzymatic function. We suggest that recessively inherited loss of function GPT2 mutations are a novel cause of intellectual disability

Expanding the Mutational Spectrum of CRLF1 in Crisponi/CISS1 Syndrome

Crisponi syndrome (CS) and cold-induced sweating syndrome type 1 (CISS1) share clinical characteristics, such as dysmorphic features, muscle contractions, scoliosis, and cold-induced sweating, with CS patients showing a severe clinical course in infancy involving hyperthermia associated with death in most cases in the first years of life. To date, 24 distinct CRLF1 mutations have been found either in homozygosity or in compound heterozygosity in CS/CISS1 patients, with the highest prevalence in Sardinia, Turkey, and Spain. By reporting 11 novel CRLF1 mutations, here we expand the mutational spectrum of CRLF1 in the CS/CISS1 syndrome to a total of 35 variants and present an overview of the different molecular and clinical features of all of them. To catalog all the 35 mutations, we created a CRLF1 mutations database, based on the Leiden Open (source) Variation Database (LOVD) system (https://grenada.lumc.nl/LOVD2/mendelian_genes/variants). Overall, the available functional and clinical data support the fact that both syndromes actually represent manifestations of the same autosomal-recessive disorder caused by mutations in the CRLF1 gene. Therefore, we propose to rename the two overlapping entities with the broader term of Crisponi/CISS1 syndrome

Early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy: new human hotfoot phenotype caused by homozygous GRID2 deletion

Purpose: The aim of this study was to identify the genetic cause of early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy in a consanguineous family. Methods: An affected 6-month-old child underwent neurological and ophthalmological examinations. Genetic analyses included homozygosity mapping, copy number analysis, conventional polymerase chain reaction, Sanger sequencing, quantitative polymerase chain reaction, and whole-exome sequencing. Expression analysis of GRID2 was performed by quantitative polymerase chain reaction and immunohistochemistry. Results: A homozygous deletion of exon 2 of GRID2 (p.G1y30_Glu-81del) was identified in the proband. GRID2 encodes an ionotropic glutamate receptor known to be selectively expressed in cerebellar Purkinje cells. Here, we demonstrated GRID2 expression in human adult retina and retinal pigment epithelium. In addition, Grid2 expression was demonstrated in different stages of murine retinal development. GRID2 immunostaining was shown in murine and human retina. Whole-exome sequencing in the proband did not provide arguments for other disease-causing mutations, supporting the idea that the phenotype observed represents a single clinical entity. Conclusion: We identified GRID2 as an underlying disease gene of early-onset autosomal recessive cerebellar ataxia with retinal dystrophy, expanding the clinical spectrum of GRID2 deletion mutants. We demonstrated for the first time GRID2 expression and localization in human and murine retina, providing evidence for a novel functional role of GRID2 in the retina. Genet Med advance online publication 14 August 201