Karak syndrome: a novel degenerative disorder of the basal ganglia and cerebellum

Two brothers are reported with early onset progressive cerebellar ataxia, dystonia, spasticity, and intellectual decline. • Neuroradiology showed cerebellar atrophy and features compatible with iron deposition in the putamen (including the “eye of the tiger sign”) and substantia nigra. • Diagnosis was compatible with pantothenate kinase associated neuropathy resulting from pantothenate kinase 2 mutation (PKAN due to PANK2) but linkage to PNAK2 was eliminated suggesting Karak syndrome to be a novel disorder. • The “eye of the tiger” sign has previously only been reported to occur in PKAN due to PKAN

Studies on mitogen regulated protein (proliferin) during murine development

Mitogen regulated protein/proliferin (MRP/PLF) is a glycoprotein with a significant percentage of positional identity in sequence with the prolactin-growth hormone family of proteins. MRP/PLF is secreted by proliferating mouse embryo cell lines and by the mouse placenta.;I developed a radioimmunoassay to examine the temporal and the spatial distribution of MRP/PLF throughout the pregnancy of CF-1 mice. The results revealed the appearance of MRP/PLF in mouse maternal plasma on the eighth day of gestation. The concentration of MRP/PLF in mouse maternal plasma reached a peak (8-10 [mu]g/ml) between the tenth and eleventh days of gestation (mid-pregnancy) and declined thereafter. Examination of various pregnant mouse tissue extracts obtained at different days in gestation revealed the presence of MRP/PLF in the placenta at a peak level (40-50 pg/[mu]g protein) between the ninth and thirteenth days of gestation; this level declined thereafter. The temporal distribution of MRP/PLF was associated with placental growth.;Other investigators have shown that MRP/PLF secreted by a cultured Chinese hamster ovary (CHO) cell line transformed with an expression vector containing mouse MRP/PLF cDNA binds the mannose 6-phosphate receptor. To examine whether MRP/PLF is cleared from maternal plasma via the mannose 6-phosphate receptors, and to gain some understanding of the structure of the carbohydrate chain on MRP/PLF, we examined the ability of MRP/PLF from maternal CF-1 mouse blood to bind to the mannose 6-phosphate receptor.;The similarity of MRP/PLF structure with prolactin and with placental lactogens, together with the temporal distribution of MRP/PLF in mouse maternal blood, allows us to propose MRP/PLF as a placental hormone. The results in this dissertation also suggest that the rate of MRP/PLF clearance from the maternal circulation via the mannose 6-phosphate receptor is developmentally regulated, and the levels of MRP/PLF are not regulated by testosterone

Karak syndrome: a novel degenerative disorder of the basal ganglia and cerebellum

We report a Jordanian Arab family where two sibsdeveloped the classical clinical and radiological fea-tures of pantothenate kinase associated neurode-generation (PKAN, formerly known as Hallervorden-Spatz disease) but in addition had an early onset cerebellar ataxia.1 2 Using polymorphic microsatellite markers we have shown that this family is not linked to the pantothenate kinase gene (PANK2) on chromosome 20.2 We hypothesise that the disorder, Karak syndrome, is novel and a member of the growing family of neurological diseases involving excess cerebral iron accumulation, for example, PKAN, neuroferritin-opathy, aceruloplasminaemia, and Friedreich’s ataxia.2–6 CLINICAL STUDIES Both affected members (fig 1, IV.1 and IV.2) were the product of a normal pregnancy and birth and had normal develop-mental milestones and progress at school until disease onset at the age of 6 years. They developed an ataxic gait that wa

Chromosome 17p-linked myasthenias stem from defects in the acetylcholine receptor epsilon-subunit gene

Objective: To identify and to characterize functionally the mutational basis of congenital myasthenic syndromes (CMS) linked to chromosome 17p. Background: A total of 37 patients belonging to 13 CMS families, 9 of them consanguineous, were investigated. All patients were linked previously to the telomeric region of chromosome 17p. Two candidate genes in this region encode synaptobrevin 2, a presynaptic protein, and the epsilon-subunit of the acetylcholine receptor (AChR). Direct sequencing of the synaptobrevin 2 gene revealed no mutations. The authors thus searched for mutations in the epsilon-subunit gene of AChR. Methods: Direct sequencing of the AChR epsilon-subunit, restriction analysis, allele-specific PCR, and expression studies in human embryonic kidney cells were performed. Results: The authors identified two previously characterized and five novel epsilon-subunit gene mutations, all homozygous, in the 13 kinships. Two of the novel mutations are truncating (epsilon 723delC and epsilon 760ins8), one is a missense mutation in the signal peptide region (epsilon V-13D), one is a missense mutation in the N-terminal extracellular domain (epsilon T51P), and one is a splice donor site mutation in intron 10 (epsilon IVS10+2T-->G). Unaffected family members have no mutations or are heterozygous. Expression studies indicate that the four novel mutations in the coding region of the gene and the most likely transcript of the splice-site mutation, which skips exon 10, are low-expressor or null mutations. Conclusions: Chromosome 17p-linked congenital myasthenic syndromes are caused by low-expressor/null mutations in the AChR epsilon-subunit gene. Mutations in this gene are a common cause of CMS in eastern Mediterranean countries

PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans.

International audienceIchthyoses comprise a heterogeneous group of genodermatoses characterized by abnormal desquamation over the whole body, for which the genetic causes of several human forms remain unknown. We used a spontaneous dog model in the golden retriever breed, which is affected by a lamellar ichthyosis resembling human autosomal recessive congenital ichthyoses (ARCI), to carry out a genome-wide association study. We identified a homozygous insertion-deletion (indel) mutation in PNPLA1 that leads to a premature stop codon in all affected golden retriever dogs. We subsequently found one missense and one nonsense mutation in the catalytic domain of human PNPLA1 in six individuals with ARCI from two families. Further experiments highlighted the importance of PNPLA1 in the formation of the epidermal lipid barrier. This study identifies a new gene involved in human ichthyoses and provides insights into the localization and function of this yet uncharacterized member of the PNPLA protein family