THERE ARE OTHERS OUT THERE!
Allelic variants.0001 PROOPIOMELANOCORTIN DEFICIENCY POMC, GLU79TER In a 3-year-old German girl
with early-onset obesity, adrenal insufficiency due to ACTH
deficiency, and red hair (609734), Krude etal. (1998) identified
compound heterozygosity for 2 mutations in exon 3of the POMC gene. A
7013G-T transversion in the paternal allele resulted in a glu79-to-ter
(G79X) substitution. Truncation of the POMC protein atcodon 79
predicted complete absence of ACTH, alpha-MSH, andbeta-endorphin,
encoded further downstream. In the maternal allele, a1-bp deletion
(nucleotide 7133) caused a frame shift predicted to disrupt the
structure of the receptor-binding core motif of ACTH and alpha-MSHand
introduced a premature termination at codon 131. Compound
heterozygosity for these 2 mutations was found not only in the
proband,the second-born daughter of the family, but also
in the first-born son who died at 7 months of age of hepatic failure
following severe cholestasis, which in the postmortem examination was
found to be caused by adrenal insufficiency due to bilateral adrenal
hypoplasia. Mutation analysis in the son was performed using a stored
newborn-screening filter-paper blood specimen
. .0002 PROOPIOMELANOCORTIN DEFICIENCY POMC, 1-BP DEL, 7133C See 176830.0001 and Krude et al. (1998)
. .0003 PROOPIOMELANOCORTIN DEFICIENCY POMC, 3804C-A In a 5-year-old German boy with early-onset obesity, adrenal insufficiency, and red hair (609734), Krude et al. (1998) found homozygosity for a 3804C-A transversion in exon 2 of the POMC gene,resulting in an additional 5-prime start codon, which abolished POMC translation. The patient was a boy with transient neonatal hypoglycemia.Birth weight was normal, but obesity was first noted at the age of 5months. After a febrile seizure, blood glucose measurement showed hypoglycemia and hyponatremia leading to an endocrinologic investigation which showed complete ACTH deficiency. With hydrocortisone substitution,the boy's subsequent development was uneventful apart from abnormal eating behavior causing progressive obesity. His intellectual and emotional assessments yielded normal results. As in the other patient(176830.0001), MRI revealed normal pituitary morphology. In a Dutch boy with early-onset obesity, red hair, and isolated ACTH deficiency (609734), Krude et al. (2003) identified homozygosity for the3804C-A transversion in the POMC gene. His parents were heterozygous for the mutation, and his brother carried only the wildtype allele. In this patient, the hair color changed to brown in the second to third years of life. Krude et al. (2003) noted that carriers of this mutation are from a circumscribed geographical area in Europe (the Netherlands,Switzerland, and Germany), suggesting a founder effect
. .0004 OBESITY, EARLY-ONSET, SUSCEPTIBILITY TO POMC, ARG236GLY Challis et al. (2002) sequenced the POMC coding region in 262 Caucasian subjects with a history of severe obesity from childhood (see 601665). Two children were found to be heterozygous for an arg236-to-gly (R236G) missense mutation, which is predicted to disrupt the dibasic cleavage site between beta-melanocyte-stimulating hormone (beta-MSH) andbeta-endorphin. Beta-TC3 cells transfected with the mutant POMC cDNA produced a mutant beta-MSH/beta-endorphin fusion protein. This fusion protein bound to the human melanocortin-4 receptor (MC4R) with an affinity similar to its natural ligands, but had a markedly reducedability to activate the receptor. This variant cosegregated with early-onset obesity in the 3-generation family of 1 of the children and was absent in 412 normal weight Caucasian controls. Combining results from 5 studies, mutations disrupting this processing site were presentin 0.88% of subjects with early-onset obesity and 0.22% of normal weight controls. The authors suggested that the R236G mutation may confer an inherited susceptibility to obesity through the production of an aberrant fusion protein that has the capacity to interfere with central melanocortin signaling
. .0005 PROOPIOMELANOCORTIN DEFICIENCY POMC, 2-BP INS, 7100GG In a Swiss girl with early-onset obesity, red hair, and isolated ACTH deficiency (609734), Krude et al. (2003) identified compound heterozygosity for a 2-bp insertion (7100GG) in exon 3 of the POMC gene and a 3804C-A transversion in exon 2 (176830.0003). Her father and mother were heterozygous for the mutations, respectively; and her brother also carried the 3804C-A transversion. The patient's hair color changed from red to brown in the second to third years of life
. .0006 PROOPIOMELANOCORTIN DEFICIENCY POMC, LYS25TER In a Slovenian boy with early-onset obesity, red hair, and isolated ACTH deficiency (609734), Krude et al. (2003) identified compound heterozygosity for a 6851A-T transversion, resulting in a lys25-to-ter(L25X) substitution, and a 1-bp deletion of nucleotide 6996(176830.0007), both in exon 3 of the POMC gene. His father and mother were heterozygous for the mutations, respectively
. .0007 PROOPIOMELANOCORTIN DEFICIENCY POMC, 1-BP DEL, NT6996 See 176830.0006 and Krude et al. (2003).
. .0002 PROOPIOMELANOCORTIN DEFICIENCY POMC, 1-BP DEL, 7133C See 176830.0001 and Krude et al. (1998)
. .0003 PROOPIOMELANOCORTIN DEFICIENCY POMC, 3804C-A In a 5-year-old German boy with early-onset obesity, adrenal insufficiency, and red hair (609734), Krude et al. (1998) found homozygosity for a 3804C-A transversion in exon 2 of the POMC gene,resulting in an additional 5-prime start codon, which abolished POMC translation. The patient was a boy with transient neonatal hypoglycemia.Birth weight was normal, but obesity was first noted at the age of 5months. After a febrile seizure, blood glucose measurement showed hypoglycemia and hyponatremia leading to an endocrinologic investigation which showed complete ACTH deficiency. With hydrocortisone substitution,the boy's subsequent development was uneventful apart from abnormal eating behavior causing progressive obesity. His intellectual and emotional assessments yielded normal results. As in the other patient(176830.0001), MRI revealed normal pituitary morphology. In a Dutch boy with early-onset obesity, red hair, and isolated ACTH deficiency (609734), Krude et al. (2003) identified homozygosity for the3804C-A transversion in the POMC gene. His parents were heterozygous for the mutation, and his brother carried only the wildtype allele. In this patient, the hair color changed to brown in the second to third years of life. Krude et al. (2003) noted that carriers of this mutation are from a circumscribed geographical area in Europe (the Netherlands,Switzerland, and Germany), suggesting a founder effect
. .0004 OBESITY, EARLY-ONSET, SUSCEPTIBILITY TO POMC, ARG236GLY Challis et al. (2002) sequenced the POMC coding region in 262 Caucasian subjects with a history of severe obesity from childhood (see 601665). Two children were found to be heterozygous for an arg236-to-gly (R236G) missense mutation, which is predicted to disrupt the dibasic cleavage site between beta-melanocyte-stimulating hormone (beta-MSH) andbeta-endorphin. Beta-TC3 cells transfected with the mutant POMC cDNA produced a mutant beta-MSH/beta-endorphin fusion protein. This fusion protein bound to the human melanocortin-4 receptor (MC4R) with an affinity similar to its natural ligands, but had a markedly reducedability to activate the receptor. This variant cosegregated with early-onset obesity in the 3-generation family of 1 of the children and was absent in 412 normal weight Caucasian controls. Combining results from 5 studies, mutations disrupting this processing site were presentin 0.88% of subjects with early-onset obesity and 0.22% of normal weight controls. The authors suggested that the R236G mutation may confer an inherited susceptibility to obesity through the production of an aberrant fusion protein that has the capacity to interfere with central melanocortin signaling
. .0005 PROOPIOMELANOCORTIN DEFICIENCY POMC, 2-BP INS, 7100GG In a Swiss girl with early-onset obesity, red hair, and isolated ACTH deficiency (609734), Krude et al. (2003) identified compound heterozygosity for a 2-bp insertion (7100GG) in exon 3 of the POMC gene and a 3804C-A transversion in exon 2 (176830.0003). Her father and mother were heterozygous for the mutations, respectively; and her brother also carried the 3804C-A transversion. The patient's hair color changed from red to brown in the second to third years of life
. .0006 PROOPIOMELANOCORTIN DEFICIENCY POMC, LYS25TER In a Slovenian boy with early-onset obesity, red hair, and isolated ACTH deficiency (609734), Krude et al. (2003) identified compound heterozygosity for a 6851A-T transversion, resulting in a lys25-to-ter(L25X) substitution, and a 1-bp deletion of nucleotide 6996(176830.0007), both in exon 3 of the POMC gene. His father and mother were heterozygous for the mutations, respectively
. .0007 PROOPIOMELANOCORTIN DEFICIENCY POMC, 1-BP DEL, NT6996 See 176830.0006 and Krude et al. (2003).
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