Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0026827 (
hypotonia
)
5,860
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Cobalamin F disease (cblF) is a rare disorder of intracellular cobalamin metabolism resulting in failure to thrive, recurrent stomatitis, skin rash, megaloblastic anemia,
hypotonia
, seizures, and intellectual disability. Data on long-term outcomes are not available. We report on the outcome of a patient with cblF disease with a frameshift mutation in the
LMBRD1
gene after 18 years of intramuscular hydroxycobalamin treatment.
...
PMID:Eighteen-year follow-up of a patient with cobalamin F disease (cblF): report and review. 2191 Feb 40
Vitamin B
12
(cobalamin (Cbl)), in the cofactor forms methyl-Cbl and adenosyl-Cbl, is required for the function of the essential enzymes methionine synthase and methylmalonyl-CoA mutase, respectively. Cbl enters mammalian cells by receptor-mediated endocytosis of protein-bound Cbl followed by lysosomal export of free Cbl to the cytosol and further processing to these cofactor forms. The integral membrane proteins
LMBD1
and ABCD4 are required for lysosomal release of Cbl, and mutations in the genes
LMBRD1
and
ABCD4
result in the cobalamin metabolism disorders
cblF
and cblJ. We report a new (fifth) patient with the cblJ disorder who presented at 7 days of age with poor feeding,
hypotonia
, methylmalonic aciduria, and elevated plasma homocysteine and harbored the mutations c.1667_1668delAG [p.Glu556Glyfs*27] and c.1295G>A [p.Arg432Gln] in the
ABCD4
gene. Cbl cofactor forms are decreased in fibroblasts from this patient but could be rescued by overexpression of either ABCD4 or, unexpectedly,
LMBD1
. Using a sensitive live-cell FRET assay, we demonstrated selective interaction between ABCD4 and
LMBD1
and decreased interaction when ABCD4 harbored the patient mutations p.Arg432Gln or p.Asn141Lys or when artificial mutations disrupted the ATPase domain. Finally, we showed that ABCD4 lysosomal targeting depends on co-expression of, and interaction with,
LMBD1
. These data broaden the patient and mutation spectrum of cblJ deficiency, establish a sensitive live-cell assay to detect the
LMBD1
-ABCD4 interaction, and confirm the importance of this interaction for proper intracellular targeting of ABCD4 and cobalamin cofactor synthesis.
...
PMID:Clinical or ATPase domain mutations in ABCD4 disrupt the interaction between the vitamin B
12
-trafficking proteins ABCD4 and LMBD1. 2857 11
