A 2-year-old boy is being evaluated at the office for failure to thrive and developmental delay. Medical history is significant for recurrent ear infections since 6 months of age. Physical examination shows corneal clouding, hepatosplenomegaly, and restricted joint mobility. Further evaluation shows deficient phosphorylation of mannose residues on certain glycoproteins in the Golgi apparatus. In unaffected patients, these proteins are normally transported to which of the following cellular locations?

Question

A 2-year-old boy is being evaluated at the office for failure to thrive and developmental delay.  Medical history is significant for recurrent ear infections since 6 months of age.  Physical examination shows corneal clouding, hepatosplenomegaly, and restricted joint mobility.  Further evaluation shows deficient phosphorylation of mannose residues on certain glycoproteins in the Golgi apparatus.  In unaffected patients, these proteins are normally transported to which of the following cellular locations?

Quizplus · Accepted Answer

11ec160b_36b1_67b3_9249_0d620b517ab8_MD0001_00 This patient has inclusion cell (I-cell) disease, an autosomal recessive lysosomal storage disorder. I-cell disease occurs due to defects in protein targeting, a process by which proteins are transported to their appropriate intra- or extracellular location. Normally, posttranslational modifications (eg, folding, glycosylation, phosphorylation) function as markers that help guide proteins to their final destination. For lysosome-bound proteins (ie, acid hydrolases), a Golgi body phosphotransferase enzyme catalyzes the phosphorylation of mannose residues on the proteins. Once tagged with mannose-6-phosphate, these proteins traverse the Golgi network and are ultimately transported to the lysosome, where they serve as catalysts for degradation of cellular components. In I-cell disease, a defective phosphotransferase enzyme results in deficient phosphorylation (ie, incorrect targeting) of mannose residues on acid hydrolases, which are then inappropriately secreted to the extracellular space. This leads to lack of degradation of lysosomal cellular debris, which accumulates within the lysosome, forming the characteristic inclusion bodies. Patients with this disorder typically have failure to thrive, respiratory tract infections, and cognitive deficits in the first year of life, along with characteristic physical features (eg, coarse facies, corneal clouding, hepatosplenomegaly). (Choice A) The endoplasmic reticulum (ER) is the site of protein synthesis prior to transport to the Golgi apparatus for protein modification and vesicular trafficking. Retrograde transport from the Golgi apparatus to the ER occurs via specialized protein-coated vesicles (eg, COPI). (Choice B) Following translation in the ER, secretory proteins traverse the Golgi apparatus and are packaged into vesicles that ultimately fuse with the plasma membrane, facilitating extracellular protein secretion. Lysosomal proteins are inappropriately transferred to the extracellular space in patients with I-cell disease. (Choice D) Most mitochondrial proteins are synthesized in the cytosol and contain specific mitochondrial targeting sequences. Translocases detect these sequences and shuttle the proteins into and between the different mitochondrial compartments. (Choice E) Peripheral membrane proteins may be modified through a process in which a hydrophobic lipid anchor is covalently attached to the protein. This process facilitates protein interaction with the plasma membrane. Educational objective: Inclusion cell disease is a lysosomal storage disorder in which a defect in protein targeting prevents the phosphorylation of mannose residues required to tag acid hydrolases for transport to lysosomes. Without these lysosomal proteins, cellular debris cannot be degraded and therefore accumulates within lysosomes, forming inclusion bodies characteristic of the disease. __________ References: Mucolipidoses overview: past, present, and future. (http://www.ncbi.nlm.nih.gov/pubmed/32957425)

A 2-Year-Old Boy Is Being Evaluated at the Office for Failure