A novel mutation in the coding region of the prosaposin gene leads to a complete deficiency of prosaposin and saposins, and is associated with a complex sphingolipidosis dominated by lactosylceramide accumulation
H. Hulkova et al., A novel mutation in the coding region of the prosaposin gene leads to a complete deficiency of prosaposin and saposins, and is associated with a complex sphingolipidosis dominated by lactosylceramide accumulation, HUM MOL GEN, 10(9), 2001, pp. 927-940
A fatal infantile storage disorder with hepatosplenomegaly and severe neuro
logical disease is described. Sphingolipids, including monohexosylceramides
(mainly glucosylceramide), dihexosylceramides (mainly lactosylceramide), g
lobotriaosyl ceramide, sulphatides, ceramides and globotetraosyl ceramide,
were stored in the tissues. In general, cholesterol and sphingomyelin level
s were unaltered. The storage process was generalized and affected a number
of cell types, with histiocytes, which infiltrated a number of visceral or
gans and the brain, especially involved. The ultrastructure of the storage
lysosomes was membranous with oligolamellar, mainly vesicular, profiles. In
frequently, there were Gaucher-like lysosomes in histiocytes. The neuropath
ology was severe and featured neuronal storage and loss with a massive depo
pulation of cortical neurons and pronounced fibrillary astrocytosis, There
was a paucity of myelin and stainable axons in the white matter with signs
of active demyelination. Immunohistochemical investigations indicated that
saposins A, B, C and D were all deficient, The patient was homozygous for a
1 bp deletion (c.803delG) within the SAP-B domain of the prosaposin gene w
hich leads to a frameshift and premature stop codon, In the heterozygous pa
rents, mutant cDNA was detected by amplification refractory mutation analys
is in the nuclear, but not the cytoplasmic, fraction of fibroblast RNA, ind
icating that the mutant mRNA was rapidly degraded. The storage process in t
he proband resembled that of a published case from an unrelated family. Sap
osins were also deficient in this case, leading to its reclassification as
prosaposin deficiency, and her mother was found to be a carrier for the sam
e c.803delG mutation. Both of the investigated families came from the same
district of eastern Slovakia.