MUCOLIPIDOSIS III, IRANIAN VARIANT FORM
ML IIIC
MUCOLIPIDOSIS IIIC
MUCOLIPIDOSIS III, VARIANT FORM
MUCOLIPIDOSIS III, COMPLEMENTATION GROUP C
ML III GAMMA
Mucolipidosis type III gamma is an autosomal recessive disorder characterized clinically by short stature, skeletal abnormalities, cardiomegaly, and developmental delay. The disorder is caused by a defect in proper lysosomal enzyme phosphorylation and localization, which results in accumulation ... Mucolipidosis type III gamma is an autosomal recessive disorder characterized clinically by short stature, skeletal abnormalities, cardiomegaly, and developmental delay. The disorder is caused by a defect in proper lysosomal enzyme phosphorylation and localization, which results in accumulation of lysosomal substrates (summary by Raas-Rothschild et al., 2000).
Encarnacao et al. (2009) reported a Portuguese patient with mucolipidosis III gamma. He had a relatively mild phenotype with onset at age 10 years, no psychomotor retardation, and survival into adulthood.
Pohl et al. (2010) reported ... Encarnacao et al. (2009) reported a Portuguese patient with mucolipidosis III gamma. He had a relatively mild phenotype with onset at age 10 years, no psychomotor retardation, and survival into adulthood. Pohl et al. (2010) reported 2 Afghan sisters and a brother, born of consanguineous parents, with mucolipidosis III gamma. All presented at about 7 years of age with progressive joint pain and stiffness, especially affecting the fingers, hip, and spine. All had myopia, but hearing and intelligence were normal. The 2 girls had short stature, but their brother had normal height. Physical examination of all 3 sibs as teenagers showed short neck, hyperlordosis of the spine, short trunks, genu valgum, flat feet, and reduced joint mobility and contractures of the shoulders, spine, and fingers. Radiographs showed signs of spondyloepiphyseal dysplasia. Cultured fibroblasts derived from the brother showed reduced activities (30 to 50%) of lysosomal enzymes compared to controls. Radiolabeling of the lysosomal enzyme cathepsin D showed that patient fibroblasts had decreased levels of newly synthesized protein, and that most (70%) of the newly synthesized protein was missorted into the medium and not targeted to lysosomes. There were also low levels of mannose-6-phosphate (M6P)-containing proteins in fibroblasts extracts. Genetic analysis identified a homozygous mutation in the GNPTG gene (607838.0009).
By sequence analysis, Raas-Rothschild et al. (2000) identified a frameshift mutation in the GNPTG gene (607838.0001) in affected members of 3 families with ML IIIC. Raas-Rothschild et al. (2000) suggested that the gamma subunit functions in lysosomal hydrolase ... By sequence analysis, Raas-Rothschild et al. (2000) identified a frameshift mutation in the GNPTG gene (607838.0001) in affected members of 3 families with ML IIIC. Raas-Rothschild et al. (2000) suggested that the gamma subunit functions in lysosomal hydrolase recognition. In 10 patients from 7 families with mucolipidosis IIIC, Persichetti et al. (2009) identified 6 novel mutations in the GNPTG gene (see, e.g., 607838.0002-607838.0006). In a Portuguese patient with mucolipidosis III gamma, Encarnacao et al. (2009) identified compound heterozygosity for 2 mutations in the GNPTG gene (607838.0007 and 607838.0008). Both GNPTG and GNPTAB mRNA transcripts were significantly decreased (10- and 2.4-fold, respectively) compared to controls. The authors suggested that the relatively mild phenotype could probably be explained by the fact that the gamma subunit does not contribute to the catalytic function of the enzyme.
The following clinical features, similar to those for mucolipidosis III alpha/beta, contribute to early diagnosis of mucolipidosis III gamma (ML III gamma) but are not by themselves diagnostic [Raas-Rothschild et al 2004, Cathey et al 2009]:...
Diagnosis
Clinical Diagnosis The following clinical features, similar to those for mucolipidosis III alpha/beta, contribute to early diagnosis of mucolipidosis III gamma (ML III gamma) but are not by themselves diagnostic [Raas-Rothschild et al 2004, Cathey et al 2009]:Family history of ML III gammaGrowth rate deceleration Joint stiffness of the fingers, shoulders, and hips Gradual mild coarsening of facial features Genu valgumNo organomegalyIn early childhood skeletal radiographs reveal mild to moderate dysostosis multiplex: Pelvis and hips. Hypoplastic iliac bones with flared iliac wings and shallow acetabula and moderate-to-severe dysplasia of the proximal femoral epiphyses giving rise to coxa valga are the most striking radiologic abnormalities in ML III gamma. Hands and feet. Diaphyses of metacarpals and phalanges are mildly shortened; carpal bones may be smaller than normal Ribs. Widening especially in lateral and frontal (costochondral junction) parts Spine. Mild generalized platyspondyly; anterior inferior hook in lower thoracic and/or higher lumbar vertebraeIn late childhood or adolescence the changes observed on skeletal radiographs worsen with the development of generalized osteopenia.Testing Activity of lysosomal hydrolases. In ML III gamma the activity of nearly all lysosomal hydrolases is up to tenfold higher in serum and other body fluids than in normal controls because mannose-6-phosphate (M6P), which is essential to proper targeting of lysosomal acid hydrolases to lysosomes, cannot be added adequately to the hydrolases (see Molecular Genetic Pathogenesis).The following lysosomal hydrolases are of most interest as their increased activity in serum and other body fluids is relevant in the differential diagnosis of ML III and lysosomal storage disorders:β-D-hexosaminidase (EC 3.2.1.52)β-D-glucuronidase (EC 3.2.1.31)β-D-galactosidase (EC 3.2.1.23)α-D-mannosidase (EC 3.2.1.24)Note: (1) Lysosomal hydrolase activity in cultured cells, such as skin fibroblasts, is low compared to control cells and permits confirmation of the diagnosis as well. (2) ML III gamma cannot be diagnosed by assay of acid hydrolases in leukocytes. (In ML II, specific activity of lysosomal enzymes is elevated in plasma, deficient in fibroblasts, and normal in leukocytes.) (3) Biochemical testing (measurement of lysosomal hydrolase activity) does not distinguish ML III alpha/beta from ML III gamma. (4) Biochemical testing cannot be used to identify heterozygotes.UDP-N-acetylglucosamine: lysosomal hydrolase N-acetylglucosamine-1-phosphotransferase enzyme (also known as GlcNAc-phosphotransferase) (EC 2.7.8.17). Demonstration of deficiency of the enzyme GlcNAc-phosphotransferase, encoded by GNPTAB (causing ML III alpha/beta) and GNPTG (causing ML III gamma) confirms the diagnosis of ML III alpha/beta and ML III gamma. Molecular Genetic TestingGene. GNPTG is the only gene in which mutation is known to cause ML III gamma.Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Mucolipidosis III GammaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityGNPTGSequence analysis
Sequence variants 2>95% 3ClinicalDeletion / duplication analysis 4Exonic, intronic, or whole-gene deletionsUnknown 5Uniparental disomy (UPD) analysis 6UPD of chromosome 16Unknown; no such reported cases to date1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice-site mutations.3. Bidirectional sequencing of the coding region and flanking intronic regions detects two disease-causing mutations in more than 95% of individuals.4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.5. The frequency of deletions that would not be detected by sequence analysis is unknown; although a few have been reported [Persichetti et al 2009].6. UPD of chromosome 16 is theoretically possible but has never been reported as causative of mucolipidosis III. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Carrier status for each parent should be confirmed: If the proband appears to be homozygous for a mutation by sequence analysis. Confirming the carrier status of the parents helps determine if the proband either (a) is a compound heterozygote for the identified disease-causing mutation and a deletion or (b) has uniparental disomy (theoretically possible but not reported to date). On rare occasion to identify affected parents who were previously undiagnosed compound heterozygotes or homozygotes [Raas-Rothschild, personal communication]. Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband requires the combination of clinical evaluation and laboratory testing. The following order of evaluation is recommended:Family history of other affected members and the presence of consanguinityIdentification of the characteristic clinical and radiographic findingsAssay of several acid hydrolases in serum (not leukocytes), such as:β-D-hexosaminidase (EC 3.2.1.52)β-D-glucuronidase (EC 3.2.1.31)β-D-galactosidase (EC 3.2.1.23)α-D-mannosidase (EC 3.2.1.24)Arylsulfatase A (EC 3.1.6.1)If the clinical findings cannot distinguish between ML III alpha beta and ML III gamma, sequence analysis of: GNPTG if the phenotype is mild ORGNPTAB if the phenotype is moderate or severeSequence analysis of the coding regions and flanking intronic segments of GNPTG and/or sequence analysis of the GNPTG cDNA if cells are available (lymphoblasts or fibroblasts). Some laboratories prefer sequence analysis of cDNA because of rapid detection of splicing mutations; in some instances, this method may be faster and more economical.Consideration of UPD analysis. UPD of chromosome 16 has never been reported as a cause of ML III gamma. Such testing may be appropriate in rare cases (e.g., when the affected child is an apparent homozygote for a mutation from one parent, the clinical suspicion is high, the other parent is not a carrier, and paternity is confirmed). Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: (1) If the affected child cannot be tested, sequence analysis of GNPTG in both carrier parents can be performed to identify the two disease-causing alleles. (2) Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family. Genetically Related (Allelic) Disorders Recently Kang et al suggested a possible role of the lysosomal M6P formation pathway in the pathogenesis of stuttering [Kang et al 2010]. It is unclear whether unaffected carriers of ML II and ML III are at increased risk of developing stuttering.
Mucolipidosis III is a slowly progressive inborn error of metabolism mainly affecting skeletal, joint, and connective tissues. Clinical onset is in early childhood and the progressive course, including cardiac involvement, results in severe functional impairment and significant morbidity. A few affected individuals may display mild cognitive impairment [Leroy 2007]; but the majority do not....
Natural History
Mucolipidosis III is a slowly progressive inborn error of metabolism mainly affecting skeletal, joint, and connective tissues. Clinical onset is in early childhood and the progressive course, including cardiac involvement, results in severe functional impairment and significant morbidity. A few affected individuals may display mild cognitive impairment [Leroy 2007]; but the majority do not.Comprehensive clinical data on ML III alpha/beta have been recently published [Cathey et al 2009], whereas only limited data are available on the natural history of ML III gamma. Thus, this review discusses the natural history of ML III in general (MLIII alpha/beta and MLIII gamma) with emphasis on ML III gamma when specifics are known. Growth. Weight and length at birth are within normal limits. Gradual slowing of growth rate begins in early childhood. Worsening hip and knee contractures add to the poor growth rate. While frank dwarfism does not occur, the height of individuals with ML III gamma is often below the tenth centile on standard growth curves.Craniofacial. Dysmorphic facial features are absent or minimal in younger children. Coarsening of facial features is more gradual in ML III gamma than ML III alpha/beta. Ophthalmologic. The corneae are clear by routine clinical inspection, but opacities that do not cause ophthalmologic impairment may be appreciated by slit-lamp examination in some persons [Traboulsi & Maumenee 1986, Schrader et al 2011]. A recent report described progressive retinitis pigmentosa in four affected consanguineous family members beginning in the third and fourth decades with decreasing night vision and leading to significant peripheral and central vision loss and night blindness [Schrader et al 2011]. Monitoring for this potential complication as affected individuals age may be warranted. Respiratory. Mild hoarseness or metallic voice has been reported.Persons with ML III gamma are small and have a small airway, reduced tracheal suppleness from stiff connective tissue, and progressive narrowing of the airway from mucosal thickening. The use of a smaller endotracheal tube than for age- and size-matched controls may be necessary. Abnormalities of the spine and ribs may limit lung capacity.Cardiovascular. Individuals with ML III are at risk for cardiac involvement. Gradual thickening and subsequent insufficiency of the mitral valve and the aortic valve are common from late childhood onward [Steet et al 2005]. Valve replacement may be required; therefore, careful follow-up is needed. Rapid progression of cardiac disease is rarely observed in ML III.Gastrointestinal. Hepatomegaly and splenomegaly are absent.Skeletal/soft connective tissue. Stiffness of finger joints, a cardinal feature, is usually the initial manifestation of the disorder. Limited range of motion of the shoulders is common early in the disease course. Genu valgum deformity occurs in all affected individuals early in the disease.Hip involvement usually develops during the end of adolescence in ML III gamma (and earlier in ML III alpha/beta). Hip involvement progresses over years, finally resulting in destruction of the proximal femoral epiphyses. Limited hip mobility and lower limb pain can be significant. Dupuytren-type palmar contractures may appear from late childhood onward. Moderate to severe claw-like flexion deformity of the fingers worsens with time.Carpal tunnel syndrome and tarsal tunnel syndrome have been reported [Umehara et al 1997, Tylki-Szymańska et al 2002, Raas-Rothschild et al 2004, Smuts et al 2009].Odontoid dysplasia and atlanto-axial dislocation were reported Umehara et al [1997] in one older individual.Neuromotor development and intellect. Neuromotor development may be delayed mainly in reaching motor milestones. Nevertheless, other aspects of development including language and learning skills fit the expected age. Affected children may require school assistance but mostly because of physical limitations. In most affected individuals cognitive function is within the normal range for age.Other. The skin may become thickened with time.Temporomandibular joint dislocation has been reported in one person, leading to difficulties in speech and feeding [Zolkipli et al 2005]. Less severe temporomandibular involvement accompanied by feeding inconvenience was also diagnosed in two individuals [Spiegel, unpublished data].
Mucolipidosis II (ML II) alpha/beta, ML III alpha/beta, and ML III gamma are all UPDGlcNAc 1-P-transferase deficiency disorders (see Nomenclature). Whereas the clinical phenotypes of ML III alpha/beta and ML III gamma can be difficult to distinguish, the severe ML II (I-cell disease) phenotype is easily differentiated....
Differential Diagnosis
Mucolipidosis II (ML II) alpha/beta, ML III alpha/beta, and ML III gamma are all UPDGlcNAc 1-P-transferase deficiency disorders (see Nomenclature). Whereas the clinical phenotypes of ML III alpha/beta and ML III gamma can be difficult to distinguish, the severe ML II (I-cell disease) phenotype is easily differentiated.ML II alpha/beta. In ML II, clinical onset is at birth with findings that can include thoracic deformity, kyphosis, clubfeet, deformed long bones, and/or dislocation of the hip(s). The skin is thickened, facial features are coarse, and gingivae are hypertrophic. All children seem to have cardiac involvement, most commonly thickening and insufficiency of the mitral valve and, less frequently, the aortic valve. Progressive mucosal thickening narrows the airways and gradual stiffening of the thoracic cage contributes to respiratory insufficiency, the most common cause of death (usually in early childhood).ML III alpha/beta. No specific ethnic predilection has been reported in ML III alpha/beta [Bargal et al 2006, Cathey et al 2009, Otomo et al 2009, Tappino et al 2009]. If the clinical diagnosis of ML III is strongly suspected and biochemical analysis shows elevated serum concentration of acid hydrolases, GNPTAB molecular genetic testing should be performed to confirm the diagnosis of ML III alpha/beta.Rheumatologic disorders are often suspected in individuals with ML III gamma because of slowly decreasing range of motion in large and small joints and increasing pain in the hips [Brik et al 1993].Rheumatoid arthritis (OMIM 180300) presents with clinical and laboratory signs of inflammation. The activities of the several lysosomal enzymes in serum are normal. Dysostosis multiplex is absent. Family history is not compatible with autosomal recessive inheritance.Progressive pseudorheumatoid dysplasia (PPD) (OMIM 208230) is caused by mutations in WISP3, the gene encoding the WNT1-inducible signaling pathways protein 3. Initially ML III gamma may be confused with PPD because of the joint stiffness but dysostosis multiplex is not present in PPD and disease course is less progressive.Lysosomal storage diseases. Clinical findings in ML III gamma overlap those observed in nearly all-late onset and/or mild forms of the following mucopolysaccharidoses (MPS):MPS I (formerly called Hurler-Scheie syndrome or Scheie syndrome)MPS II (Hunter syndrome) MPS IV B (Morquio disease type B) (OMIM 253010)MPS VI B (Maroteaux-Lamy disease type B) (OMIM 253200)MPS VII B (Sly disease type B) (OMIM 253220)Specific biochemical and molecular genetic testing distinguishes between the mucopolysaccharidoses.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with ML III gamma, the following evaluations are recommended:...
Management
Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with ML III gamma, the following evaluations are recommended:Basic assessmentGrowth parametersPain assessmentOrthopedic and functional assessmentsPsycho-developmental evaluation to follow the individual’s developmental progress and program appropriate managementSkeletal surveyMetabolic bone disease assessment including evaluation of bone densitometry by DEXA studies and evaluation of biomarkers reflecting bone metabolism [Robinson et al 2002] CardiacClinical examinationECGEchocardiographyOphthalmologic evaluation including slit lamp examination, fundoscopy, and visual acuityMedical genetics consultation for genetic counseling and reproductive decision makingTreatment of Manifestations Supportive and symptomatic management is indicated. Psychosocial support of patients and families is recommended.No known measures are effective in treating the progressive limitation of motion in large and small joints. Physiotherapy intervention programs need to be adapted to the affected individual’s needs. Short sessions of aqua therapy that are “low impact” in regard to joint and tendon strain are usually well tolerated.Later in the disease course bone pain of variable intensity may become a frequent complaint. Management of pain in the hips is required. In older adolescents and adults with milder ML III gamma, bilateral hip replacement has been successful. Casts (especially of the hands) during the night hours are usually well tolerated and seem to improve daily functions. Carpal tunnel signs and rarely tarsal tunnel symptoms may require surgical tendon release procedures for temporary relief [Smuts et al 2009].In severe cases, when significant valvular dysfunction disrupts ventricular function, valve replacement should be seriously considered.Prevention of Secondary Complications Anesthesia. As with all storage diseases, anesthesia in ML III gamma must be well planned. Because of concerns about airway management, surgical intervention should be undertaken only in tertiary care settings with pediatric anesthesiologists and intensive care physicians.The anesthetic team should be aware of the following issues: Persons with ML III gamma are small and have a small airway, reduced tracheal suppleness from stiff connective tissue, and progressive narrowing of the airway from mucosal thickening. The use of a smaller endotracheal tube than for age- and size-matched controls is necessary. Fiberoptic intubation must be available. Persons with ML III gamma have short necks and atlanto-axial instability has been reported [Umehara et al 1997]. Jaw and neck movement can be limitedAbnormalities of the spine and ribs can limit the individual’s capacity to breathe and fully expand the lungs. Antibiotic prophylaxis. Persons with valvular involvement should be given antibiotic prophylaxis before minor and major surgical procedures (including dental procedures) to prevent bacterial endocarditis.Surveillance Young children with ML III gamma and their families usually benefit from out-patient clinic visits once a year, unless cardiac and/or respiratory monitoring need more frequent attention. Orthopedic assessment should be done at least once a year, with more frequent follow-up visits if any deterioration is observed. Annual ophthalmologic assessment should address possible ophthalmologic changes. If necessary, an ERG should be considered to better evaluate for retinal impairment.During yearly visits, attention should be paid to pain relief, daily functional abilities, and psychological interventions. Although cardiac manifestations are usually asymptomatic, monitoring for progressive valvular insufficiency using echocardiography should occur at least once a year. Surveillance for metabolic bone disease includes DEXA scan in five-year intervals.Agents/Circumstances to AvoidVigorous stretching exercises are not recommended because they are ineffective, painful, and may damage the surrounding joint capsule and adjacent tendons.Evaluation of Relatives at RiskIf both disease-causing alleles have been identified in the family, testing of at-risk sibs can be pursued. Note, however, that early diagnosis of affected individuals does not delay or halt disease progression [Author, personal observation].See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under Investigation Several individuals with ML III alpha/beta have been treated with monthly intra-venous administration of pamidronate, a bisphosphonate. At present information is insufficient about when in the ML III alpha/beta disease course or at what age such treatment should be initiated [Robinson et al 2002; Sillence, personal communication]. In a consensus meeting on the use of bisphosphonate therapy in oligosaccharidoses doubts were raised regarding its usefulness in ML III gamma [MPS Society 2008].Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Mucolipidosis III Gamma: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDGNPTG16p13.3
N-acetylglucosamine-1-phosphotransferase subunit gammaGNPTG @ LOVDGNPTGData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Mucolipidosis III Gamma (View All in OMIM) View in own window 252605MUCOLIPIDOSIS III GAMMA 607838N-ACETYLGLUCOSAMINE-1-PHOSPHOTRANSFERASE, GAMMA SUBUNIT; GNPTGMolecular Genetic Pathogenesis Newly synthesized lysosomal hydrolases have mannose 6-phosphate (M6P) residues that function as recognition markers for specific receptors required for lysosomal targeting. The M6P marker is generated in the Golgi apparatus by the sequential action of two enzymes.In the first step N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) transfers GlcNac-1-phosphate to the C6 position mannose residues of acid hydrolases.In the second step, N-acetylglucosamine-1-phosphodiester α-N-acetylglucosminidase (uncovering enzyme) removes N-acetylglucosamine residues thus exposing the M6P residues in order to correctly bind to their lysosomal membrane receptor.GlcNAc-phosphotransferase is made up of three different subunits: alpha, beta, and gamma in a hexameric α2β2γ2 subunit complex [Bao et al 1996]. The three subunits are the product of two genes: GNPTAB and GNPTG. GNPTAB, the gene encoding the alpha and beta subunits, maps to chromosome 12q23 [Tiede et al 2005, Kudo et al 2006]. Mutations in this gene result in mucolipidosis type III alpha/beta [Bargal et al 2006] and ML II.GNPTG, the gene encoding the gamma subunit of GlcNAc-phospotransferse located on chromosome 16p13.3 was identified in 2000 [Raas-Rothschild et al 2000]. Mutations in this gene result in mucolipidosis type III gamma [Raas-Rothschild et al 2004]. The exact role of the γ subunit in the function of GlcNAc-phosphotransferase is not yet understood. Recent studies have proposed that it is important in the proper maintenance of α and β subunits in the GlcNAc-phosphotransferase complex [Pohl et al 2009].Normal allelic variants. GNPTG contains 11 exons that span 11.13 kb of genomic DNA. It encodes a 305-amino acid protein. After cleavage of the 24-amino acid signal peptide, the mature protein (γ subunit) forms disulfide-linked homodimers that become glycosylated at Asn88 and Asn115 [Raas-Rothschild et al 2000, Tiede et al 2004].Pathologic allelic variants. More than 16 disease-causing mutations have been reported (Table 2). They include missense, nonsense, splice site and frameshift mutations as well as small intragenic deletions and insertions. In individuals with ML III gamma, homozygous or compound heterozygous mutations are detected. To date no correlation between severity of the disease and type of mutation has been reported. The list of mutations and their resultant protein changes are described in Table 2.Table 2. Selected GNPTG Pathologic Allelic Variants View in own windowDNA Nucleotide Change (Alias 1)Protein Amino Acid Change ReferenceReference Sequencesc.318-1G>C (IVS5-1G>C)(Exon 6 skipping)Raas-Rothschild et al [2004]NM_032520.3 NP_115909.1c.196C>Tp.Arg66XRaas-Rothschild et al [2004]c.316G>Ap.Gly106SerRaas-Rothschild et al [2004]c.333G>Ap.Trp111XPersichetti et al [2009]c.347_349delACAp.Asn116delTiede et al [2004] Persichetti et al [2009]c.379_391del13p.Asp127Profs*31Raas-Rothschild et al [2004]c.523dupC (522insC)p.Leu175Profs*24Raas-Rothschild et al [2000]c.608_609insC (608insC)p.Gln203Hisfs*4Raas-Rothschild et al [2004]c.609+28_610-16del33Persichetti et al [2009]c.610-1C>T (IVS8-1G>T)Encarnação et al [2009]c.610-2A>GPersichetti et al [2009]c.611delGp.Gly204Alafs*6Persichetti et al [2009]c.619_620insTp.Lys207Ilefs*8Pohl et al [2009]c.639delTp.Phe213Leufs*7Encarnação et al [2009]c.640_667del28p.Glu214Lysfs*37Persichetti et al [2009]c.857C>Tp.Thr286MetPersichetti et al [2009]See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal gene product. The exact role of the γ subunit in the function of GlcNAc-phosphotransferase is not entirely understood. Recent studies have proposed that it is important in the proper maintenance of α and β subunits in the GlcNAc-phosphotransferase complex [Pohl et al 2009].Abnormal gene product. Unknown