Isolated Methylmalonic Acidemia (MMA) comprises a relatively common and heterogeneous group of inborn errors of metabolism. In order to create mouse models of MMA to resemble the pathogenic mutations seen in patients, the NHGRI scientist used genome editing to generate new mutants of the Mmut allele - p.R106C. This allele recapitulates a missense mutation seen in multiple patients with the disorder. Of note and emphasis is the fact that there are no transgene cassettes or other alternations to the Mmut locus in these new mouse models.

Propionic acidemia (PA) is an autosomal recessive metabolic disorder caused by mutations in either Propionyl-CoA carboxylase alpha (PCCA) or Propionyl-CoA carboxylase beta (PCCB). The products of these genes form the alpha and beta subunits of the enzyme propionyl-Co A carboxylase (PCC), a critically important mitochondrial enzyme involved in the catabolism of branched chain amino acids.

Deficiency of the enzyme in methylmalonyl-CoA mutase (MMUT) results is a life-threatening disease, methylmalonic acidemia (MMA), that carries high rates of morbidity and mortality.

Methylmalonic acidemia (MMA) is an autosomal recessive disorder, caused by the deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT). It is characterized by metabolic instability, multiorgan pathology, and poor prognosis for long-term survival. Deletion of Mut in mice results in neonathal lethality, thus, to overcome this limitation, we have generated novel transgenic mice that have the Mut knockout background but express the Mut gene under the control of a muscle-specific creatine kinase promoter (Mut-/- Tg INS-Mck-Mut).

Methylmalonic acidemia (MMA) is an autosomal recessive disorder, caused by the deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT). It is characterized by metabolic instability, multiorgan pathology, and poor prognosis for long-term survival. A well-characterized human mutation, p.G717V, has been introduced into mice. This mutation has been characterized as a "pure" adenosylcobalamin Km mutation. NHGRI scientist have used site-directed mutagenesis to generate the homologous mouse mutation, p.G715V, and verified the kinetic properties of this mutant enzyme in vitro.

Methylmalonic acidemia (MMA) is an autosomal recessive disorder caused by the deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT). It is characterized by metabolic instability, multiorgan pathology, and poor prognosis for long-term survival. To study MMA caused by MUT deficiency, a series of murine models have been constructed using gene targeting and analyzed. The model is a full knock out of the mouse Mut gene that produces neonatal lethality on the C57Bl6/Sv129 background.

Isolated Methylmalonic Acidemia (MMA) comprises a relatively common and heterogeneous group of inborn errors of metabolism. The most common cause of isolated MMA is genetic deficiency of the enzyme methylmalonyl-coA mutase (MUT), which, unfortunately for the affected patients, is also the most clinically severe. NHGRI scientist have discovered biomarkers previously described cytokines that has never been associated with MMA or propionic acidemia (PA) such as FGF-21 (fibroblast like-growth factor - 21).

Propionic acidemia (PA) is an autosomal recessive metabolic disorder caused by mutations in either PCCA or PCCB. The products of these genes form the alpha and beta subunits of the enzyme propionyl-Co A carboxylase (PCC), a critically important mitochondrial enzyme involved in the catabolism of branched chain amino acids. NHGRI scientist have developed a new set of synthetic PCCA genes that can be used to treat PA caused by PCCA mutation(s).

This technology includes a new set of synthetic PCCB genes that can be used to treat propionic acidemia (PA) caused by propionyl-coA carboxylase beta (PCCB) mutations. The amino acid sequence of PCCB was reverse translated, using a variety of algorithms and expert input, to generate novel DNA sequences encoding PCCB (synPCCB1-5) expected to have increased expression.

This technology includes mouse models (heterozygous for the knock-in (KI) and homozygous for the knock-out (KO)) to be used as research reagents and to study molecular mechanisms and potential therapies for Familial Mediterranean fever (FMF). FMF is the prototype of a group of inherited disorders characterized by recurring, spontaneous episodes of fever and localized inflammation. The gene responsible for FMF is composed of 10 exons encoding a 781 amino acid protein known as pyrin.