title: When Mucolipidosis III meets Mucolipidosis II: GNPTA gene mutations in 24 patients.
abstract: Mucolipidosis II (ML II) and Mucolipidosis type III (ML III) are autosomal recessive disorders of lysosomal hydrolases trafficking due to the deficiency of the multimeric enzyme, UDP-N-acetylglucosamine-1-phosphotransferase. The alpha/beta subunits encoded by the GNPTA gene is the catalytic subunit of the enzyme while the gamma recognition subunit is encoded by the GNPTAG gene. We report the molecular analysis of GNPTA in 21 families with ML II and 3 families with ML III. The ML II mutant genotypes included three splice-site mutations [IVS1-2A>G; IVS17+1G>A; IVS18+1G>A] in seven Palestinian, Israeli Arab-Muslims, and Turkish patients; a two base pair deletion [c.3503_4delTC] [corrected] in 11 patients from Israel, Turkey, and Ireland; two nonsense mutations [c.2533C>T (Q845X); c.3613C>T (R1205X)], in a Turkish and an Arab-Muslim patient from the Nablus area, respectively, and an insertion mutation [c.2916insT] in a patient from Nablus. The ML III mutant genotypes included a splice-site mutation [IVS17+6T>G] in two patients from Irish/Scottish origin who were compound heterozygous for a nonsense mutation [c.3565C>T (R1189X)] and the deletion mutation [c.3503_4delTC] [corrected] respectively. The third ML III patient from France was compound heterozygous for a missense mutation [c.1196C>T] and the same deletion [c.3503_4delTC] [corrected] found homozygous in 11 ML II patients. The 21 ML II patients were homozygous while the three ML III patients were compound heterozygous for mutations in GNPTA. The results of this study confirm that ML II or ML III phenotype is not due to the localization of the mutations, but rather to the severity of the mutations, ML II and ML III might be allelic, and ML III is genetically heterogeneous. We suggest that the diseases due to mutations in GNPTA represent a clinical continuum between ML III and ML II, and the classification of these diseases should be based on the age of onset, clinical symptoms, and severity.
authors.affiliation: Department of Human Genetics, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Bargal
authors.forename: Marsha
authors.initials: M
authors.lastname: Zeigler
authors.forename: Bassam
authors.initials: B
authors.lastname: Abu-Libdeh
authors.forename: Vivi
authors.initials: V
authors.lastname: Zuri
authors.forename: Hanna
authors.initials: H
authors.lastname: Mandel
authors.forename: Ziva
authors.initials: Z
authors.lastname: Ben Neriah
authors.forename: Fiona
authors.initials: F
authors.lastname: Stewart
authors.forename: Nursel
authors.initials: N
authors.lastname: Elcioglu
authors.forename: Tareq
authors.initials: T
authors.lastname: Hindi
authors.forename: Martine
authors.initials: M
authors.lastname: Le Merrer
authors.forename: Gideon
authors.initials: G
authors.lastname: Bach
authors.forename: Annick
authors.initials: A
authors.lastname: Raas-Rothschild
mesh_terms: D002675:Child, Preschool; D003241:Consanguinity; D005091:Exons; D005190:Family; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D009081:Mucolipidoses / Q000235:genetics*; D009154:Mutation; D022821:RNA Splice Sites; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics*
chemical_list: D022821:RNA Splice Sites; D017855:Transferases (Other Substituted Phosphate Groups); C511050:GNPTAB protein, human