ABSTRACT
Mast syndrome is an autosomal recessive, complicated form of hereditary spastic paraplegia with dementia that is present at high frequency among the Old Order Amish. Subtle childhood abnormalities may be present, but the main features develop in early adulthood. The disease is slowly progressive, and cerebellar and extrapyramidal signs are also found in patients with advanced disease. Patients have a thin corpus callosum and white-matter abnormalities, as seen on magnetic resonance imaging. Using an extensive Amish pedigree, we have mapped the Mast syndrome locus (SPG21) to a small interval of chromosome 15q22.31 that encompasses just three genes. Sequence analysis of the three transcripts revealed that all 14 affected cases were homozygous for a single base-pair insertion (601insA) in the acid-cluster protein of 33 kDa (ACP33) gene. This frameshift results in the premature termination (fs201-212X213) of the encoded product, which is designated "maspardin" (Mast syndrome, spastic paraplegia, autosomal recessive with dementia), and has been shown elsewhere to localize to intracellular endosomal/trans-Golgi transportation vesicles and may function in protein transport and sorting.
Subject(s)
Carrier Proteins/genetics , Dementia/complications , Dementia/genetics , Mutation/genetics , Spastic Paraplegia, Hereditary/complications , Spastic Paraplegia, Hereditary/genetics , Adaptor Proteins, Signal Transducing , Adult , Amino Acid Sequence , Base Sequence , Brain/abnormalities , Brain/diagnostic imaging , Carrier Proteins/chemistry , Chromosomes, Human, Pair 15/genetics , DNA Mutational Analysis , Dementia/diagnostic imaging , Dementia/pathology , Ethnicity/genetics , Female , Genes, Recessive/genetics , Haplotypes/genetics , Humans , Lod Score , Magnetic Resonance Imaging , Male , Middle Aged , Models, Molecular , Molecular Sequence Data , Pedigree , Protein Conformation , Protestantism , Radiography , Spastic Paraplegia, Hereditary/diagnostic imaging , Spastic Paraplegia, Hereditary/pathology , SyndromeABSTRACT
Troyer syndrome (TRS) is an autosomal recessive complicated hereditary spastic paraplegia (HSP) that occurs with high frequency in the Old Order Amish. We report mapping of the TRS locus to chromosome 13q12.3 and identify a frameshift mutation in SPG20, encoding spartin. Comparative sequence analysis indicates that spartin shares similarity with molecules involved in endosomal trafficking and with spastin, a molecule implicated in microtubule interaction that is commonly mutated in HSP.
