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• W2104976235 abstract "Diagnosis of lysosomal storage diseases (LSDs) can be problematic in atypical cases where clinical phenotype may overlap with other genetically distinct disorders. In addition, LSDs may result from mutations in genes not yet implicated in disease. Thus, there are individuals that are diagnosed with apparent LSD based upon clinical criteria where the gene defect remains elusive. The objective of this study was to determine whether comparative proteomics approaches could provide useful insights into such cases. Most LSDs arise from mutations in genes encoding lysosomal proteins that contain mannose 6-phosphate, a carbohydrate modification that acts as a signal for intracellular targeting to the lysosome. We purified mannose 6-phosphorylated proteins by affinity chromatography and estimated relative abundance of individual proteins in the mixture by spectral counting of peptides detected by tandem mass spectrometry. Our rationale was that proteins that are decreased or absent in patients compared with controls could represent candidates for the primary defect, directing biochemical or genetics studies. On a survey of brain autopsy specimens from 23 patients with either confirmed or possible lysosomal disease, this approach identified or validated the genetic basis for disease in eight cases. These results indicate that this protein expression approach is useful for identifying defects in cases of undiagnosed lysosomal disease, and we demonstrated that it can be used with more accessible patient samples, e.g. cultured cells. Furthermore this approach was instrumental in the identification or validation of mutations in two lysosomal proteins, CLN5 and sulfamidase, in the adult form of neuronal ceroid lipofuscinosis. Diagnosis of lysosomal storage diseases (LSDs) can be problematic in atypical cases where clinical phenotype may overlap with other genetically distinct disorders. In addition, LSDs may result from mutations in genes not yet implicated in disease. Thus, there are individuals that are diagnosed with apparent LSD based upon clinical criteria where the gene defect remains elusive. The objective of this study was to determine whether comparative proteomics approaches could provide useful insights into such cases. Most LSDs arise from mutations in genes encoding lysosomal proteins that contain mannose 6-phosphate, a carbohydrate modification that acts as a signal for intracellular targeting to the lysosome. We purified mannose 6-phosphorylated proteins by affinity chromatography and estimated relative abundance of individual proteins in the mixture by spectral counting of peptides detected by tandem mass spectrometry. Our rationale was that proteins that are decreased or absent in patients compared with controls could represent candidates for the primary defect, directing biochemical or genetics studies. On a survey of brain autopsy specimens from 23 patients with either confirmed or possible lysosomal disease, this approach identified or validated the genetic basis for disease in eight cases. These results indicate that this protein expression approach is useful for identifying defects in cases of undiagnosed lysosomal disease, and we demonstrated that it can be used with more accessible patient samples, e.g. cultured cells. Furthermore this approach was instrumental in the identification or validation of mutations in two lysosomal proteins, CLN5 and sulfamidase, in the adult form of neuronal ceroid lipofuscinosis. The genetic bases for numerous human hereditary diseases are well established (1Scriver C.R. The Metabolic and Molecular Bases of Inherited Disease. 8th Ed. McGraw-Hill, New York2001Google Scholar), but there are some for which the defective genes remain to be identified. For example, in the Online Mendelian Inheritance in Man database (2McKusick V.A. Mendelian Inheritance in Man: a Catalog of Human Genes and Genetic Disorders. 12th Ed. Johns Hopkins University Press, Baltimore1998Google Scholar), there are currently listed over a thousand Mendelian clinical phenotypes of unknown molecular basis. Understanding the molecular basis for disease is essential for genetic screening and developing effective therapy, but identifying individual gene defects can represent a significant challenge. This is particularly true of orphan diseases where patient populations may be small or clinically poorly defined and thus may not be readily amenable to traditional genetics approaches. Proteomics methods provide an alternative route in the investigation of such unsolved genetic diseases and can provide disease gene candidates for further analysis in two different ways. First, comparative proteomics can uncover proteins that are altered in abundance or other properties in specimens from affected individuals, and these may potentially be encoded by the mutant gene. Second, descriptive proteomics can identify novel proteins with known or predicted properties or expression patterns that may associate them with diseases of unknown etiology. Such approaches can be applicable to small cohorts or even individual cases and have been particularly useful in the investigation of lysosomal storage diseases (LSDs) 1The abbreviations used are:LSDlysosomal storage diseaseMPSmucopolysaccharidosisNCLneuronal ceroid lipofuscinosisLINCLlate infantile neuronal ceroid lipofuscinosisANCLadult neuronal ceroid lipofuscinosisMan-6-Pmannose 6-phosphateMPRMan-6-P receptorSGSHN-sulfoglucosamine sulfohydrolase (sulfamidase)CTSDcathepsin DTPP1tripeptidyl-peptidase 1PPT1palmitoyl-protein thioesterase 1LTQlinear trap quadrupoleGPMGlobal Proteome MachineCNScentral nervous systemOMIMOnline Mendelian Inheritance in Man1The abbreviations used are:LSDlysosomal storage diseaseMPSmucopolysaccharidosisNCLneuronal ceroid lipofuscinosisLINCLlate infantile neuronal ceroid lipofuscinosisANCLadult neuronal ceroid lipofuscinosisMan-6-Pmannose 6-phosphateMPRMan-6-P receptorSGSHN-sulfoglucosamine sulfohydrolase (sulfamidase)CTSDcathepsin DTPP1tripeptidyl-peptidase 1PPT1palmitoyl-protein thioesterase 1LTQlinear trap quadrupoleGPMGlobal Proteome MachineCNScentral nervous systemOMIMOnline Mendelian Inheritance in Man (for a review, see Ref. 3Sleat D.E. Jadot M. Lobel P. Lysosomal proteomics and disease..Proteomics Clin. Appl. 2007; 1: 1134-1146Crossref PubMed Scopus (19) Google Scholar).LSDs most commonly result from mutations in genes encoding lysosomal enzymes and accessory proteins. As one of the primary functions of the lysosome is the degradation of cellular macromolecules (for a review, see Ref. 4Holtzman E. Lysosomes. Plenum Press, New York1989Crossref Google Scholar), a hallmark of these diseases is an accumulation of undigested substrates and other storage material within the lysosomes in cells of affected individuals. Most LSD genes have been identified using classical biochemical or genetics methods, but there are some clinically defined LSDs for which the defective genes are not known. Proteomics approaches have been instrumental in the discovery of gene defects in three such human diseases. For Niemann-Pick C type 2 disease (5Naureckiene S. Sleat D.E. Lackland H. Fensom A. Vanier M.T. Wattiaux R. Jadot M. Lobel P. Identification of HE1 as the second gene of Niemann-Pick C disease..Science. 2000; 290: 2298-2301Crossref PubMed Scopus (689) Google Scholar) and mucopolysaccharidosis (MPS) IIIC (6Fan X. Zhang H. Zhang S. Bagshaw R.D. Tropak M.B. Callahan J.W. Mahuran D.J. Identification of the gene encoding the enzyme deficient in mucopolysaccharidosis IIIC (Sanfilippo disease type C)..Am. J. Hum. Genet. 2006; 79: 738-744Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar), pathogenic mutations were found in genes encoding novel lysosomal proteins that were discovered in proteomics surveys. In classical late infantile neuronal ceroid lipofuscinosis (LINCL), the mutant gene product was identified as a spot that was present on two-dimensional gels of extracts from brain autopsy specimens of controls but not of affected individuals (7Sleat D.E. Donnelly R.J. Lackland H. Liu C.G. Sohar I. Pullarkat R.K. Lobel P. Association of mutations in a lysosomal protein with classical late-infantile neuronal ceroid lipofuscinosis..Science. 1997; 277: 1802-1805Crossref PubMed Scopus (502) Google Scholar).In addition to these clinically defined but unsolved diseases, there are individual cases with histopathological evidence of lysosomal storage where gene defects have not been identified. There are several possible reasons for the lack of a definitive genetic diagnosis in these cases. First, given the heterogeneity and overlap in clinical presentation of LSDs, especially when dealing with atypical alleles, no obvious underlying gene defect may be apparent. Second, genetic validation may be difficult to establish if mutations occur outside of coding regions or if they cannot be distinguished from harmless polymorphisms. Third, disease may result from mutations in genes that encode proteins that are not currently thought to be associated with LSDs.In this study, we conducted a comparative analysis of purified mannose 6-phosphate (Man-6-P) glycoproteins from brain autopsy samples from potential LSD cases of unsolved or ambiguous etiology to investigate the molecular basis of disease. Our rationale was that we may identify lysosomal proteins that are altered in terms of expression in cases compared with controls and that this information may provide valuable clues to the cause of disease. Central to this approach is the ability to selectively isolate lysosomal proteins for analysis. Most newly synthesized lysosomal enzymes are glycoproteins that receive a specialized carbohydrate modification, Man-6-P, that is recognized by Man-6-P receptors (MPRs). The MPRs bind both newly synthesized lysosomal proteins in the Golgi and extracellular lysosomal proteins at the cell surface, and they travel to an acidic endolysosomal compartment where the low pH directs dissociation of receptor and ligand. From an analytical perspective, immobilized MPRs can be used to affinity purify proteins containing Man-6-P, and this has facilitated numerous studies of the lysosomal proteome (for a review, see Ref. 8Lübke T. Lobel P. Sleat D.E. Proteomics of the lysosome..Biochim. Biophys. Acta. 2009; 1793: 625-635Crossref PubMed Scopus (188) Google Scholar).In this report, we demonstrate that mass spectrometry-based proteomics profiling can successfully lead to a definitive genetic diagnosis in difficult cases where conventional methods were not fruitful. In addition to providing a proof of principle for a clinical proteomics approach to LSDs, this approach was instrumental in the discovery of two lysosomal proteins in which defects may underlie the adult form of NCL, a neurodegenerative disease of currently uncertain basis.DISCUSSIONIn this study, we used spectral counting-based protein expression profiling of purified Man-6-P glycoproteins to identify gene defects in LSD of unknown or ambiguous genetic basis. Although successful in a number of cases, this approach did not identify the gene defect in all samples examined, and this is to be expected for several reasons. First, although most defects resulting in LSDs occur within genes encoding soluble, Man-6-P-containing glycoproteins, this is not always the case. Second, some mutations may result in stable but inactive protein products, and these may also be missed. Third, proteins that are differentially expressed throughout the CNS could potentially be missed in this analysis, which was primarily focused on cerebrum. Fourth, in proteins of low relative abundance, gene defects may go unnoticed if a pathogenic loss of a protein cannot be distinguished from variability in measurement or natural biological heterogeneity. Although the analysis of rare components of mixtures is challenging, application of more sensitive, quantitative MS methods (e.g. use of isotope-labeled standards with triple quadrupole or high resolution MS) rather than spectral counting should help to diminish such errors. Regardless this proof-of-concept study for proteomics profiling using label-free methods and a linear ion trap mass spectrometer proved to be remarkably successful, identifying or confirming lysosomal defects in eight of 26 of the cases investigated (Table III).Although most LSD alleles resulted in the loss of protein product, the example of UMB 784 highlights the possibility that some mutations may allow for significant expression levels (>1% of normal) of the mutant protein. Thus, in searching for candidates in cases where defects are not obvious, it may also be helpful to identify proteins whose expression deviates significantly from the normal. We achieved this here with a χ2 analysis (supplemental Table 5). Expression levels of some proteins (e.g. palmitoyl-protein thioesterase 1 (PPT1) and CTSD) varied widely and were frequently low even in samples with confirmed defects in other genes. However, other proteins were expressed at relatively constant levels in all samples, and a significant decrease in such proteins may be relevant. Examples include cathepsin C and α-N-acetylglucosaminidase as proteins that were significantly reduced in HSB 2356 and CABM-BR36, respectively, and these may be worth further investigation in these cases. It is also worth noting that TPP1 was significantly reduced in a case of Alexander disease (UMB 613), possibly indicating a secondary effect of disease.An important discovery to emerge from this study was the identification of new atypical variants of unrelated lysosomal diseases that were diagnosed as ANCL. Disease course in ANCL is extremely variable, but typically onset is at about 30 years of age. It is neurodegenerative, associated with seizures and progressive dementia, and results in premature death on average 13 years after onset (for a review, see Ref. 22Goebel H.H. Mole S.E. Lake B.D. The Neuronal Ceroid Lipofuscinoses (Batten Disease). IOS Press, Amsterdam1999Google Scholar). The defective gene in the majority of ANCL cases remains to be identified, although several have been found to harbor mutations in PPT1 (23van Diggelen O.P. Thobois S. Tilikete C. Zabot M.T. Keulemans J.L. van Bunderen P.A. Taschner P.E. Losekoot M. Voznyi Y.V. Adult neuronal ceroid lipofuscinosis with palmitoyl-protein thioesterase deficiency: first adult-onset patients of a childhood disease..Ann. Neurol. 2001; 50: 269-272Crossref PubMed Scopus (101) Google Scholar, 24Ramadan H. Al-Din A.S. Ismail A. Balen F. Varma A. Twomey A. Watts R. Jackson M. Anderson G. Green E. Mole S.E. Adult neuronal ceroid lipofuscinosis caused by deficiency in palmitoyl protein thioesterase 1..Neurology. 2007; 68: 387-388Crossref PubMed Scopus (38) Google Scholar). In this study, we investigated four ANCL cases. In one case, the protein profiling approach validated earlier genetics studies, and in another it led to the identification of the defective gene.In an earlier study of an ANCL case of unknown etiology, CABM-BR19, we purified Man-6-P glycoproteins from a brain specimen from this patient and used two-dimensional gel electrophoresis to compare with controls, but obvious defects were not apparent (25Sleat D.E. Lackland H. Wang Y. Sohar I. Xiao G. Li H. Lobel P. The human brain mannose 6-phosphate glycoproteome: a complex mixture composed of multiple isoforms of many soluble lysosomal proteins..Proteomics. 2005; 5: 1520-1532Crossref PubMed Scopus (78) Google Scholar). A genetics screen of potential disease gene candidates revealed missense changes in the gene encoding CLN5,2 a soluble lysosomal Man-6-P glycoprotein of unknown function. However, in the absence of either an activity assay for CLN5 or reliable immunoreagents, it was not clear whether these changes represented pathogenic alleles or harmless polymorphisms. Mass spectrometric profiling of purified Man-6-P glycoproteins revealed that CLN5 was absent in this case, strongly suggesting that these changes represent the cause of disease. CLN5 defects normally cause a variant form of LINCL with onset at around 4–7 years of age and survival into the second or third decade of life (18Savukoski M. Klockars T. Holmberg V. Santavuori P. Lander E.S. Peltonen L. CLN5, a novel gene encoding a putative transmembrane protein mutated in Finnish variant late infantile neuronal ceroid lipofuscinosis..Nat. Genet. 1998; 19: 286-288Crossref PubMed Scopus (243) Google Scholar), although variants with slightly later onset (∼9 years of age) have been reported (26Cannelli N. Nardocci N. Cassandrini D. Morbin M. Aiello C. Bugiani M. Criscuolo L. Zara F. Striano P. Granata T. Bertini E. Simonati A. Santorelli F.M. Revelation of a novel CLN5 mutation in early juvenile neuronal ceroid lipofuscinosis..Neuropediatrics. 2007; 38: 46-49Crossref PubMed Scopus (36) Google Scholar, 27Pineda-Trujillo N. Cornejo W. Carrizosa J. Wheeler R.B. Múnera S. Valencia A. Agudelo-Arango J. Cogollo A. Anderson G. Bedoya G. Mole S.E. Ruíz-Linares A. A CLN5 mutation causing an atypical neuronal ceroid lipofuscinosis of juvenile onset..Neurology. 2005; 64: 740-742Crossref PubMed Scopus (44) Google Scholar). For the ANCL case analyzed here, onset of disease was at 20 years of age, and the patient survived until 33 years old (17Goebel H.H. Schochet S.S. Jaynes M. Gutmann L. Ultrastructure of the retina in adult neuronal ceroid lipofuscinosis..Acta Anat. 1998; 162: 127-132Crossref PubMed Scopus (9) Google Scholar). Neither of the CLN5 mutations (C126Y and Y374C)2 have been identified previously. Although Mendelian inheritance of these mutations remains to be demonstrated, the facts that CLN5 was found in all other cases except this one and that loss of CLN5 presents as an NCL disease together provide a highly convincing argument that this represents the causative defect. It is worth noting that in this study we found CLN5 to be a relatively abundant component of the mixture of proteins purified from controls when they were analyzed by LC-MS/MS, but we did not detect this protein when the same samples were fractionated by two-dimensional gel electrophoresis and the resulting spots were analyzed by either peptide mass fingerprinting or MALDI-TOF/TOF mass spectrometry (25Sleat D.E. Lackland H. Wang Y. Sohar I. Xiao G. Li H. Lobel P. The human brain mannose 6-phosphate glycoproteome: a complex mixture composed of multiple isoforms of many soluble lysosomal proteins..Proteomics. 2005; 5: 1520-1532Crossref PubMed Scopus (78) Google Scholar). It is possible that CLN5 is specifically lost during the additional gel electrophoresis step or that the CLN5 peptides are not readily ionized using MALDI-based methods, but regardless, this result does demonstrate that LC-MS/MS is well suited to our current application.SGSH defects are normally diagnosed as MPSIIIA (28Scott H.S. Blanch L. Guo X.H. Freeman C. Orsborn A. Baker E. Sutherland G.R. Morris C.P. Hopwood J.J. Cloning of the sulphamidase gene and identification of mutations in Sanfilippo A syndrome..Nat. Genet. 1995; 11: 465-467Crossref PubMed Scopus (123) Google Scholar) with onset that is around 2 years of age, severe neurodegeneration between 6 and 10 years of age, and survival typically into the second or third decade of life (29van de Kamp J.J. Niermeijer M.F. von Figura K. Giesberts M.A. Genetic heterogeneity and clinical variability in the Sanfilippo syndrome (types A, B, and C)..Clin. Genet. 1981; 20: 152-160Crossref PubMed Scopus (147) Google Scholar). Less severe SGSH alleles that result in extended lifespan have been reported (19Beesley C.E. Young E.P. Vellodi A. Winchester B.G. Mutational analysis of Sanfilippo syndrome type A (MPS IIIA): identification of 13 novel mutations..J. Med. Genet. 2000; 37: 704-707Crossref PubMed Google Scholar, 20Bunge S. Ince H. Steglich C. Kleijer W.J. Beck M. Zaremba J. van Diggelen O.P. Weber B. Hopwood J.J. Gal A. Identification of 16 sulfamidase gene mutations including the common R74C in patients with mucopolysaccharidosis type IIIA (Sanfilippo A)..Hum. Mutat. 1997; 10: 479-485Crossref PubMed Scopus (55) Google Scholar, 30Di Natale P. Balzano N. Esposito S. Villani G.R. Identification of molecular defects in Italian Sanfilippo A patients including 13 novel mutations..Hum. Mutat. 1998; 11: 313-320Crossref PubMed Scopus (51) Google Scholar, 31Gabrielli O. Coppa G.V. Bruni S. Villani G.R. Pontarelli G. Di Natale P. An adult Sanfilippo type A patient with homozygous mutation R206P in the sulfamidase gene..Am. J. Med. Genet. A. 2005; 133A: 85-89Crossref PubMed Scopus (22) Google Scholar, 32Meyer A. Kossow K. Gal A. Steglich C. Mühlhausen C. Ullrich K. Braulke T. Muschol N. The mutation p.Ser298Pro in the sulphamidase gene (SGSH) is associated with a slowly progressive clinical phenotype in mucopolysaccharidosis type IIIA (Sanfilippo A syndrome)..Hum. Mutat. 2008; 29: 770Crossref PubMed Scopus (35) Google Scholar), although onset is during childhood; thus these cases are not diagnosed as ANCL. (There is one previous report of adult onset MPSIIIA, but neurodegeneration was not a feature in this case (33Van Hove J.L. Wevers R.A. Van Cleemput J. Moerman P. Sciot R. Matthijs G. Schollen E. de Jong J.G. Carey W.F. Muller V. Nicholls C. Perkins K. Hopwood J.J. Late-Onset visceral presentation with cardiomyopathy and without neurological symptoms of adult Sanfilippo A syndrome..Am. J. Med. Genet A. 2003; 118A: 382-387Crossref PubMed Scopus (25) Google Scholar).) Therefore, SGSH deficiencies have not previously been associated with ANCL. In this study, mass spectrometric protein profiling suggested that SGSH was missing in ANCL case HSB 4165, and this led to the identification of mutations in the SGSH gene. The mutations identified (E355K and S298P) are both previously described pathogenic alleles (19Beesley C.E. Young E.P. Vellodi A. Winchester B.G. Mutational analysis of Sanfilippo syndrome type A (MPS IIIA): identification of 13 novel mutations..J. Med. Genet. 2000; 37: 704-707Crossref PubMed Google Scholar, 20Bunge S. Ince H. Steglich C. Kleijer W.J. Beck M. Zaremba J. van Diggelen O.P. Weber B. Hopwood J.J. Gal A. Identification of 16 sulfamidase gene mutations including the common R74C in patients with mucopolysaccharidosis type IIIA (Sanfilippo A)..Hum. Mutat. 1997; 10: 479-485Crossref PubMed Scopus (55) Google Scholar), one of which is associated with attenuated disease (20Bunge S. Ince H. Steglich C. Kleijer W.J. Beck M. Zaremba J. van Diggelen O.P. Weber B. Hopwood J.J. Gal A. Identification of 16 sulfamidase gene mutations including the common R74C in patients with mucopolysaccharidosis type IIIA (Sanfilippo A)..Hum. Mutat. 1997; 10: 479-485Crossref PubMed Scopus (55) Google Scholar, 32Meyer A. Kossow K. Gal A. Steglich C. Mühlhausen C. Ullrich K. Braulke T. Muschol N. The mutation p.Ser298Pro in the sulphamidase gene (SGSH) is associated with a slowly progressive clinical phenotype in mucopolysaccharidosis type IIIA (Sanfilippo A syndrome)..Hum. Mutat. 2008; 29: 770Crossref PubMed Scopus (35) Google Scholar), which is consistent with our findings. It is interesting to note that although autofluorescent inclusions are not generally regarded as a defining feature of MPSIIIA they have been observed in some patients (34Wisniewski K. Rudelli R. Laure-Kamionowska M. Sklower S. Houck Jr., G.E. Kieras F. Ramos P. Wisniewski H.M. Braak H. Sanfilippo disease, type A with some features of ceroid lipofuscinosis..Neuropediatrics. 1985; 16: 98-105Crossref PubMed Scopus (24) Google Scholar), which may explain possible confusion with NCLs.These results indicate that clinically defined ANCL is not a distinct genetic entity and raise the possibility that other autosomal recessive cases actually represent late onset, slowly progressing variants of NCLs and unrelated LSDs. In support of this, an earlier review of cases published as ANCL (35Berkovic S.F. Carpenter S. Andermann F. Andermann E. Wolfe L.S. Kufs' disease: a critical reappraisal..Brain. 1988; 111: 27-62Crossref PubMed Scopus (196) Google Scholar) concluded that almost half either appeared atypical, had clinical features characteristic of other LSDs, or lacked a key feature of ANCL, neuronal storage. It is worth noting that both the CLN5 and SGSH-deficient cases appear to fulfill the requirements for diagnosis as ANCL outlined by Berkovic et al. (35Berkovic S.F. Carpenter S. Andermann F. Andermann E. Wolfe L.S. Kufs' disease: a critical reappraisal..Brain. 1988; 111: 27-62Crossref PubMed Scopus (196) Google Scholar) with electron microscopy revealing fingerprint/curvilinear profiles for the CLN5 deficiency (CABM-BR19) (17Goebel H.H. Schochet S.S. Jaynes M. Gutmann L. Ultrastructure of the retina in adult neuronal ceroid lipofuscinosis..Acta Anat. 1998; 162: 127-132Crossref PubMed Scopus (9) Google Scholar) and osmiophilic deposits for the SGSH deficiency (HSB 4165; specimen report). This indicates that the genetic origin of even bona fide ANCL is more varied than previously thought.In LSDs, there are changes in lysosomal activities that are secondary to a primary defect, and these changes are likely disease-specific. Therefore we investigated the possibility that the global pattern of expression of lysosomal proteins may provide clues to the etiology of disease. In Fig. 4, we constructed a hierarchical cluster of cases based upon the expression profiles of lysosomal proteins. There are four broad groupings. In Group 1, control cases were found to be closely related, and they clustered together. All four adult NCL cases appear to be related despite differences in genetic basis (i.e. CLN5, SGSH, or unknown), and together with the case of classical MPSIIIA (SGSH), they fall within Group 1 with the controls. It is possible, for ANCL at least, that the apparent similarity to the control cases may reflect relatively subtle lysosomal alterations that result in a later onset and more slowly progressing disease than is seen in the other, more severe cases in our cohort. Group 2 comprises mainly potential LSD cases and does not include NCLs. Interestingly demyelination appears to be a common theme in most of the cases in this group. Groups 3 and 4 appear to be most different from the controls, and these largely consist of established LINCL cases and NCL cases of indeterminate origin. These groupings may provide useful clues to the identification of disease genes in cases where the mutant gene product is inactive yet stable and thus levels may not be diminished as with CTSD in ovine NCL (36Tyynelä J. Sohar I. Sleat D.E. Gin R.M. Donnelly R.J. Baumann M. Haltia M. Lobel P. A mutation in the ovine cathepsin D gene causes a congenital lysosomal storage disease with profound neurodegeneration..EMBO J. 2000; 19: 2786-2792Crossref PubMed Scopus (201) Google Scholar). As an example, although SGSH levels were not found to be decreased, further investigation of this protein may be justified in the two unsolved ANCL cases CABM-BR8 and HSB2356 considering how closely they align with the confirmed SGSH deficiencies.In conclusion, the application of mass spectrometry-based methods for protein expression profiling represents a promising approach to the investigation of LSDs of unknown or ambiguous etiology. In addition to the direct identification of gene defects, the application of proteomics approaches to globally interrogate potential relationships between different diseases may also provide unique insights into both the biology of these diseases and the functions of the respective lysosomal proteins. The genetic bases for numerous human hereditary diseases are well established (1Scriver C.R. The Metabolic and Molecular Bases of Inherited Disease. 8th Ed. McGraw-Hill, New York2001Google Scholar), but there are some for which the defective genes remain to be identified. For example, in the Online Mendelian Inheritance in Man database (2McKusick V.A. Mendelian Inheritance in Man: a Catalog of Human Genes and Genetic Disorders. 12th Ed. Johns Hopkins University Press, Baltimore1998Google Scholar), there are currently listed over a thousand Mendelian clinical phenotypes of unknown molecular basis. Understanding the molecular basis for disease is essential for genetic screening and developing effective therapy, but identifying individual gene defects can represent a significant challenge. This is particularly true of orphan diseases where patient populations may be small or clinically poorly defined and thus may not be readily amenable to traditional genetics approaches. Proteomics methods provide an alternative route in the investigation of such unsolved genetic diseases and can provide disease gene candidates for further analysis in two different ways. First, comparative proteomics can uncover proteins that are altered in abundance or other properties in specimens from affected individuals, and these may potentially be encoded by the mutant gene. Second, descriptive proteomics can identify novel proteins with known or predicted properties or expression patterns that may associate them with diseases of unknown etiology. Such approaches can be applicable to small cohorts or even individual cases and have been particularly useful in the investigation of lysosomal storage diseases (LSDs) 1The abbreviations used are:LSDlysosomal storage diseaseMPSmucopolysaccharidosisNCLneuronal ceroid lipofuscinosisLINCLlate infantile neuronal ceroid lipofuscinosisANCLadult neuronal ceroid lipofuscinosisMan-6-Pmannose 6-phosphateMPRMan-6-P receptorSGSHN-sulfoglucosamine sulfohydrolase (sulfamidase)CTSDcathepsin DTPP1tripeptidyl-peptidase 1PPT1palmitoyl-protein thioesterase 1LTQlinear trap quadrupoleGPMGlobal Proteome MachineCNScentral nervous systemOMIMOnline Mendelian Inheritance in Man1The abbreviations used are:LSDlysosomal storage diseaseMPSmucopolysaccharidosisNCLneuronal ceroid lipofuscinosisLINCLlate infantile neurona" @default.
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• W2104976235 date "2009-07-01" @default.
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• W2104976235 title "Mass Spectrometry-based Protein Profiling to Determine the Cause of Lysosomal Storage Diseases of Unknown Etiology" @default.
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• W2104976235 doi "https://doi.org/10.1074/mcp.m900122-mcp200" @default.
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