[Show abstract][Hide abstract] ABSTRACT: We analyzed four families that presented with a similar condition characterized by congenital microcephaly, intellectual disability, progressive cerebral atrophy, and intractable seizures. We show that recessive mutations in the ASNS gene are responsible for this syndrome. Two of the identified missense mutations dramatically reduce ASNS protein abundance, suggesting that the mutations cause loss of function. Hypomorphic Asns mutant mice have structural brain abnormalities, including enlarged ventricles and reduced cortical thickness, and show deficits in learning and memory mimicking aspects of the patient phenotype. ASNS encodes asparagine synthetase, which catalyzes the synthesis of asparagine from glutamine and aspartate. The neurological impairment resulting from ASNS deficiency may be explained by asparagine depletion in the brain or by accumulation of aspartate/glutamate leading to enhanced excitability and neuronal damage. Our study thus indicates that asparagine synthesis is essential for the development and function of the brain but not for that of other organs.
[Show abstract][Hide abstract] ABSTRACT: We studied five individuals from three Jewish Bukharian families affected by an apparently autosomal-recessive form of hereditary spastic paraparesis accompanied by severe intellectual disability, fluctuating central hypoventilation, gastresophageal reflux disease, wake apnea, areflexia, and unique dysmorphic features. Exome sequencing identified one homozygous variant shared among all affected individuals and absent in controls: a 1 bp frameshift TECPR2 deletion leading to a premature stop codon and predicting significant degradation of the protein. TECPR2 has been reported as a positive regulator of autophagy. We thus examined the autophagy-related fate of two key autophagic proteins, SQSTM1 (p62) and MAP1LC3B (LC3), in skin fibroblasts of an affected individual, as compared to a healthy control, and found that both protein levels were decreased and that there was a more pronounced decrease in the lipidated form of LC3 (LC3II). siRNA knockdown of TECPR2 showed similar changes, consistent with aberrant autophagy. Our results are strengthened by the fact that autophagy dysfunction has been implicated in a number of other neurodegenerative diseases. The discovered TECPR2 mutation implicates autophagy, a central intracellular mechanism, in spastic paraparesis.
Full-text · Article · Nov 2012 · The American Journal of Human Genetics
[Show abstract][Hide abstract] ABSTRACT: Sarcosinemia is an autosomal recessive metabolic trait manifested by relatively high concentrations of sarcosine in blood and urine. Sarcosine is a key intermediate in 1-carbon metabolism and under normal circumstances is converted to glycine by the enzyme sarcosine dehydrogenase. We encountered six families from two different descents (French and Arab), each with at least one individual with elevated levels of sarcosine in blood and urine. Using the "candidate gene approach" we sequenced the gene encoding sarcosine dehydrogenase (SARDH), which plays an important role in the conversion of sarcosine to glycine, and found four different mutations (P287L, V71F, R723X, R514X) in three patients. In an additional patient, we found a uniparental disomy in the region of SARDH gene. In two other patients, we did not find any mutations in this gene. We have shown for the first time that mutations in the SARDH gene are associated with sarcosinemia. In addition, our results indicate that other genes are most probably involved in the pathogenesis of this condition.
[Show abstract][Hide abstract] ABSTRACT: To define the frequency of the R92Q tumor necrosis factor receptor-associated periodic syndrome (TRAPS) mutation in patients with familial Mediterranean fever (FMF) and to study the role of this mutation in FMF.
Ninety-two FMF patients and 250 controls were genotyped for the R92Q mutation. The frequency of R92Q was assessed among 5 groups of FMF patients.
R92Q was found in 6% of the controls, with an especially high carrier rate among Moroccan Jews (8%). R92Q was found in 3 (3.2%) of the 92 FMF patients, 1 homozygous for the MEFV M694V mutation and 2 heterozygous for M694V. All 3 patients showed partial response to colchicine. R92Q was not found in patients unresponsive to colchicine, nor was it found in patients with amyloidosis or in patients with FMF-like disease without MEFV mutations.
The frequency of the R92Q mutation in FMF patients is comparable with that of controls. Despite the fact that TRAPS and FMF share common biochemical pathways, we found no evidence for an interaction between these two genes.