Publications

Recovery from Friend virus 3 (Rfv3) is a single autosomal gene encoding a resistance trait that influences retroviral neutralizing antibody responses and viremia. Despite extensive research for 30 years, the molecular identity of Rfv3 has remained elusive. Here, we demonstrate that Rfv3 is encoded by Apobec3. Apobec3 maps to the same chromosome region as Rfv3 and has broad inhibitory activity against retroviruses, including HIV. Not only did genetic inactivation of Apobec3 convert Rfv3-resistant mice to a susceptible phenotype, but Apobec3 was also found to be naturally disabled by aberrant messenger RNA splicing in Rfv3-susceptible strains. The link between Apobec3 and neutralizing antibody responses highlights an Apobec3-dependent mechanism of host protection that might extend to HIV and other human retroviral infections.

Cardioviruses comprise a genus of picornaviruses that cause severe illnesses in rodents, but little is known about the prevalence, diversity, or spectrum of disease of such agents among humans. A single cardiovirus isolate, Saffold virus, was cultured in 1981 in stool from an infant with fever. Here, we describe the identification of a group of human cardioviruses that have been cloned directly from patient specimens, the first of which was detected using a pan-viral microarray in respiratory secretions from a child with influenza-like illness. Phylogenetic analysis of the nearly complete viral genome (7961 bp) revealed that this virus belongs to the Theiler's murine encephalomyelitis virus (TMEV) subgroup of cardioviruses and is most closely related to Saffold virus. Subsequent screening by RT-PCR of 719 additional respiratory specimens [637 (89%) from patients with acute respiratory illness] and 400 cerebrospinal fluid specimens from patients with neurological disease (aseptic meningitis, encephalitis, and multiple sclerosis) revealed no evidence of cardiovirus infection. However, screening of 751 stool specimens from 498 individuals in a gastroenteritis cohort resulted in the detection of 6 additional cardioviruses (1.2%). Although all 8 human cardioviruses (including Saffold virus) clustered together by phylogenetic analysis, significant sequence diversity was observed in the VP1 gene (66.9%-100% pairwise amino acid identities). These findings suggest that there exists a diverse group of novel human Theiler's murine encephalomyelitis virus-like cardioviruses that hitherto have gone largely undetected, are found primarily in the gastrointestinal tract, can be shed asymptomatically, and have potential links to enteric and extraintestinal disease.

CONTEXT

Proopiomelanocortin (POMC) is the precursor to five biologically active peptides, including ACTH produced in the anterior pituitary and alpha-MSH produced in the hypothalamus. Mutations that inactivate the POMC gene have been described in children, causing a pleiotropic syndrome that includes secondary hypocortisolism, severe obesity, and variable changes in skin and hair pigmentation.

OBJECTIVE

We describe a female patient of North African ancestry, homozygous for a frameshift mutation in the POMC gene (6922InsC) that impairs the production of all melanocortin peptides, and that is associated with novel clinical features. Repeated clinical investigations from birth to age 18 yr are presented.

RESULT

ACTH deficiency was diagnosed at birth. Hyperphagia and obesity became apparent before 2 yr of age and rapidly progressed [body mass index (BMI) Z-score, +7 sd at 2 yr, +9.7 sd at 13 yr; BMI, 50 kg/m(2) at 18 yr). At puberty, the patient developed alterations in the somatotropic, gonadotropic, and thyroid axes necessitating hormonal replacement. Surprisingly, there were no obvious pigmentary features; neither the hair color nor measurements of skin reflectance distinguished between the patient and unaffected family members. However, chemical analysis of hair pigment revealed increased production of both pheomelanin and eumelanin.

CONCLUSION

Molecular genetic abnormalities of POMC should always be considered in patients with early onset adrenal insufficiency and obesity, even in the presence of normal pigmentation and multiple pituitary hormone anomalies.