We describe a patient with 46,XY partial gonadal dysgenesis (PGD) who presented with polyneuropathy. Sural nerve pathology revealed peculiar findings characterized by extensive minifascicular formation within the endoneurium and with a decreased density of myelinated fibers. We found, in the patient, a homozygous missense mutation (ATG-->ACG) at the initiating codon in exon 1 of the desert hedgehog (DHH) gene, which predicts a failure of translation of the gene. The same heterozygous mutation was found in the patient's father. This is the first report of a human DHH gene mutation, and the findings demonstrate that mutation of the DHH gene may cause 46, XY PGD associated with minifascicular neuropathy.

We describe a 40-year-old Japanese man with a 3-year history of vesiculopustular lesions resembling subcorneal pustular dermatosis. Histopathology showed subcorneal pustules containing a few acantholytic cells, and direct immunofluorescence disclosed IgA deposition in the intercellular space of the upper epidermis. Circulating IgA autoantibodies of very low titre were also demonstrated by indirect immunofluorescence. A novel cDNA transfection technique clearly detected IgA autoantibodies reactive with human desmocollin-1. Combined therapy with dapsone and etretinate improved the skin lesions. We review the clinical features of 49 patients in the literature who presented with vesiculopustular lesions and intraepidermal IgA deposition.

Hedgehog proteins are important in the development of the nervous system. As Desert hedgehog (Dhh) is involved in the development of peripheral nerves and is expressed in adult nerves, it may play a role in the maintenance of adult nerves and degeneration and regeneration after injury. We firstly investigated the Dhh-receptors, which are expressed in mouse adult nerves. The Dhh receptor patched(ptc)2 was detected in adult sciatic nerves using RT-PCR, however, ptc1 was undetectable under the same experimental condition. Using RT-PCR in purified cultures of mouse Schwann cells and fibroblasts, we found ptc2 mRNA in Schwann cells, and at much lower levels, in fibroblasts. By immunohistochemistry, Ptc2 protein was seen on unmyelinated nerve fibers. Then we induced crush injury to the sciatic nerves of wild-type (WT) and dhh-null mice and the distal stumps of injured nerves were analyzed morphologically at different time points and expression of dhh and related receptors was also measured by RT-PCR in WT mice. In dhh-null mice, degeneration of myelinated fibers was more severe than in WT mice. Furthermore, in regenerated nerves of dhh-null mice, minifascicular formation was even more extensive than in dhh-null intact nerves. Both dhh and ptc2 mRNA levels were down-regulated during the degenerative phase postinjury in WT mice, while levels rose again during the phase of nerve regeneration. These results suggest that the Dhh-Ptc2 signaling pathway may be involved in the maintenance of adult nerves and may be one of the factors that directly or indirectly determines the response of peripheral nerves to injury.

Glucagon-like peptide-1 (GLP-1), in the form of either GLP-1-(7-36)amide or GLP-1-(7-37), has been shown to potently stimulate insulin release in a glucose-dependent manner and is suggested to be a physiological incretin. To explore the mechanisms by which GLP-1-(7-36)amide stimulates insulin release, we investigated its action on the cytosolic free Ca2+ concentration ([Ca2+]i) in single rat pancreatic beta-cells by the dual wavelength microfluorometry with fura-2. In the presence of 8.3 mM glucose, GLP-1-(7-36)amide at a concentration as low as 3 x 10(-12) M produced a rapid transient increase in [Ca2+]i in some of the single beta-cells. GLP-1-(7-36)amide at 10(-11) M or more evoked the [Ca2+]i response in the majority of beta-cells. In the presence of 2.8 mM glucose, GLP-1-(7-36)amide was without effect. The [Ca2+]i response to GLP-1-(7-36)amide was completely and reversibly inhibited under Ca(2+)-free conditions and by 1 microM nitrendipine, a blocker of L-type Ca2+ channels. Elevation of cAMP in beta-cells by either 10 microM forskolin, an activator of adenylyl cyclase, or 5 mM (bu)2cAMP (db-cAMP) produced an increase in [Ca2+]i similar to that caused by GLP-1-(7-36)amide. The db-cAMP-induced increase in [Ca2+]i was also completely blocked by nitrendipine. In the continuous presence of GLP-1-(7-36)amide and after the transient [Ca2+]i increase it elicited, db-cAMP failed to evoke the [Ca2+]i response. It is concluded that GLP-1-(7-36)amide at physiological concentrations and a rise in cAMP increase [Ca2+]i in pancreatic beta-cells by enhancing the activity of L-type Ca2+ channels in the beta-cell plasma membrane. It is suggested that the cAMP-operative mechanism is involved in the GLP-1-(7-36)amide action to increase [Ca2+]i in beta-cells.

No abstract