ABSTRACT
Sialidosis is an autosomal recessive disease caused by the genetic deficiency of lysosomal sialidase, which catalyzes the hydrolysis of sialoglycoconjugates. The disease is associated with progressive impaired vision, macular cherry-red spots and myoclonus (sialidosis type I) or with skeletal dysplasia, Hurler-like phenotype, dysostosis multiplex, mental retardation and hepatosplenomegaly (sialidosis type II). We have analyzed the genomic DNA from nine sialidosis patients of multiple ethnic origin in order to find mutations responsible for the enzyme deficiency. The activity of the identified variants was studied by transgenic expression. One patient had a frameshift mutation (G623delG deletion), which introduced a stop codon, truncating 113 amino acids. All others had missense mutations: G679G-->A (Gly227Arg), C893C-->T (Ala298Val), G203G-->T (Gly68Val), A544A-->G (Ser182Gly) C808C-->T (Leu270Phe) and G982G-->A (Gly328Ser). We have modeled the three-dimensional structure of sialidase based on the atomic coordinates of the homologous bacterial sialidases, located the positions of mutations and estimated their potential effect. This analysis showed that five mutations are clustered in one region on the surface of the sialidase molecule. These mutations dramatically reduce the enzyme activity and cause a rapid intralysosomal degradation of the expressed protein. We hypothesize that this region may be involved in the interface of sialidase binding with lysosomal cathepsin A and/or beta-galactosidase in their high-molecular-weight complex required for the expression of sialidase activity in the lysosome.
Subject(s)
Lysosomes/enzymology , Mucolipidoses/enzymology , Mucolipidoses/genetics , Neuraminidase/chemistry , Neuraminidase/genetics , Adolescent , Adult , Amino Acid Sequence , Animals , Base Sequence , Binding Sites , COS Cells , Carboxypeptidases/metabolism , Cathepsin A , Child , Child, Preschool , DNA/metabolism , Exons , Female , Humans , Infant , Male , Models, Molecular , Molecular Sequence Data , Mutation , Mutation, Missense , Phenotype , Sequence Homology, Amino Acid , beta-Galactosidase/metabolismABSTRACT
Two brothers born to a healthy, consanguineous Spanish couple have a syndrome of Möbius sequence with involvement of cranial nerves V, VI, VII, IX, and XII, central nervous system malformations; characteristic face with creased earlobes, short philthrum, and a short, arched upper lip, skeletal anomalies with short sternum and delayed bone maturation, hypogenitalism, and profound mental retardation. We suggest that this is a new multiple congenital anomalies condition and mental retardation (MCA/MR) syndrome with autosomic recessive inheritance.
Subject(s)
Abnormalities, Multiple/genetics , Bone and Bones/abnormalities , Brain/abnormalities , Cranial Nerves/abnormalities , Facial Paralysis/genetics , Hypogonadism/genetics , Brain/pathology , Child , Consanguinity , Cranial Nerves/pathology , Female , Humans , Magnetic Resonance Imaging , Male , Nuclear Family , Spain , SyndromeABSTRACT
A retrospective study on 834 newborns of low birth weight, 2,500 grs., or less over a total of 19,869 live newborns during the year 1973 is presented. They are divided into low birth weight compatible with gestational age and low birth weight for gestational age when birth weight is lower than 10th percentile of Lubchenco's chart. Each of these groups is subdivided in three parts: First part refers to coincidence of frequence of different ethiologic factors or causes of low birth weight (maternal, gestational, placental and termination of pregnancy). The second part has its object in the clinical appraisal of the state at birth of these low birth weight newborns (fetal-obstetric evaluation of Velasco-Cándano, neonatal Apgar scoring, respiratory evaluation by Silvermann-Andersen and evaluation of external maturaty according to Usher). Third part of the study relates the morbility-mortality rate, need for admission, presence of congenital anomalies and autopsy findings in each of these groups of low birth weight newborns. Relation among all these estimated parameters is made presenting some conclusions reached.
