FAHN/SPG35 : a narrow phenotypic spectrum across disease classifications

The endoplasmic reticulum enzyme fatty acid 2-hydroxylase (FA2H) plays a major role in the formation of 2-hydroxy glycosphingolipids, main components of myelin. FA2H deficiency in mice leads to severe central demyelination and axon loss. In humans it has been associated with phenotypes from the neurodegeneration with brain iron accumulation (fatty acid hydroxylase-associated neurodegeneration, FAHN), hereditary spastic paraplegia (HSP type SPG35) and leukodystrophy (leukodystrophy with spasticity and dystonia) spectrum. We performed an in-depth clinical and retrospective neurophysiological and imaging study in a cohort of 19 cases with biallelic FA2H mutations. FAHN/SPG35 manifests with early childhood onset predominantly lower limb spastic tetraparesis and truncal instability, dysarthria, dysphagia, cerebellar ataxia, and cognitive deficits, often accompanied by exotropia and movement disorders. The disease is rapidly progressive with loss of ambulation after a median of 7 years after disease onset and demonstrates little interindividual variability. The hair of FAHN/SPG35 patients shows a bristle-like appearance; scanning electron microscopy of patient hair shafts reveals deformities (longitudinal grooves) as well as plaque-like adhesions to the hair, likely caused by an abnormal sebum composition also described in a mouse model of FA2H deficiency. Characteristic imaging features of FAHN/SPG35 can be summarized by the WHAT' acronym: white matter changes, hypointensity of the globus pallidus, ponto-cerebellar atrophy, and thin corpus callosum. At least three of four imaging features are present in 85% of FA2H mutation carriers. Here, we report the first systematic, large cohort study in FAHN/SPG35 and determine the phenotypic spectrum, define the disease course and identify clinical and imaging biomarkers

Activation of c-myc promoter P1 by immunoglobulin κ gene enhancers in Burkitt lymphoma: functional characterization of the intron enhancer motifs kB, E box 1 and E box 2 and of the 3' enhancer motif PU.

eregulated expression of the proto-oncogene c-myc in Burkitt lymphoma (BL) cells carrying a t(2;8) translocation is mediated by a synergistic interaction of the translocated immunoglobulin (Ig) kappa gene intron (kappa Ei) and 3' (kappa E3') enhancers and characterized by a strong activation of the promoter P1, We have investigated the functional role of distinct kappa enhancer sequence motifs in P1 activation on both minichromosomes and reporter gene constructs, Stable and transient transfections of BL cells revealed critical roles of the kappa Ei and kappa E3' elements kappa B and PU, respectively, Joint mutation of kappa B and PU completely abolished P1 activity, implying that an interaction of kappa B- and PU-binding factors is essential for the enhancer synergism, Mutation of the E box 1 and E box 2 motifs markedly decreased P1 activity in transient but not in stable transfection experiments. Co-expression of the NF-kappa B subunit p65(RelA) and Sp1, an essential factor for P1 transcription, in Drosophila melanogaster SL2 cells synergistically enhanced promoter activity. Our results support a model which proposes cross-talk between promoter and enhancer binding factors as the basic mechanism for kappa enhancer-mediated c-myc activation in BL cell

An isoform of hPANK2, deficient in pantothenate kinase-associated neurodegeneration, localizes to mitochondria.

Mutations in the human PANK2 gene have been shown to occur in autosomal-recessive pantothenate kinase-associated neurodegeneration, a syndrome originally described by Hallervorden and Spatz. The kinase catalyses the first and rate-limiting step in the biosynthesis of coenzyme A, a key molecule in energy metabolism. We have determined the exon-intron structure of the hPANK2 gene and identified two alternatively used first exons. The resulting transcripts encode distinct isoforms of hPANK2, one of which carries an N-terminal extension with a predicted mitochondrial targeting signal. An in vitro import assay and in vivo immunolocalization experiments demonstrate a mitochondrial localization of this isoform. We conclude that the symptoms observed in pantothenate kinase-associated neurodegeneration are caused by a deficiency of the mitochondrial isoform and postulate the existence of a complete intramitochondrial pathway for de novo synthesis of coenzyme A