Maspardin Is Mutated in Mast Syndrome, a Complicated Form of Hereditary Spastic Paraplegia Associated with Dementia

• Published in: American journal of human genetics 2003-11, Vol.73 (5), p.1147-1156
• Main Authors: Simpson, Michael A., Cross, Harold, Proukakis, Christos, Pryde, Anna, Hershberger, Ruth, Chatonnet, Arnaud, Patton, Michael A., Crosby, Andrew H.
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Adult; Amino Acid Sequence; Base Sequence; Biological and medical sciences; Brain - abnormalities; Brain - diagnostic imaging; Carrier Proteins - chemistry; Carrier Proteins - genetics; Chromosomes, Human, Pair 15 - genetics; Computer Science; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dementia - complications; Dementia - diagnostic imaging; Dementia - genetics; Dementia - pathology; DNA Mutational Analysis; Ethnicity - genetics; Female; Genes, Recessive - genetics; Haplotypes - genetics; Humans; Life Sciences; Lod Score; Magnetic Resonance Imaging; Male; Medical sciences; Middle Aged; Models, Molecular; Molecular Sequence Data; Mutation - genetics; Neurology; Pedigree; Protein Conformation; Protestantism; Radiography; Spastic Paraplegia, Hereditary - complications; Spastic Paraplegia, Hereditary - diagnostic imaging; Spastic Paraplegia, Hereditary - genetics; Spastic Paraplegia, Hereditary - pathology; Syndrome
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/379522

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.