Honors & Awards

  • Paul and Yuanbi Ramsay Endowed Postdoctoral Fellow, Child Health Research Institute (CHRI), Stanford University (2014)
  • Elliot Goldings Award in Rheumatology, University of Texas Southwestern Medical School (2010)
  • Chrysalis Project, American Academy of Allergy, Asthma, and Immunology (AAAAI) (2008)
  • Fellow, Postbaccalaureate Intramural Research Training Award, Division of Intramural Research, National Institutes of Health (1999-2001)

Boards, Advisory Committees, Professional Organizations

  • President, Society for Pediatric Research, Junior Section (2015 - Present)
  • President-Elect, Society for Pediatric Research, Fellows Section (2014 - 2015)

Professional Education

  • Bachelor of Arts, Pomona College (1999)
  • Doctor of Medicine, Univ of Texas Southwestern Medical Center (2010)
  • Doctor of Philosophy, Univ of Texas Southwestern Medical Center (2010)
  • Residency, University of Texas Southwestern Medical Center/Children's Medical Center Dallas, Pediatrics (2013)
  • Fellowship, Stanford University/Lucile Packard Children's Hospital, Pediatric Hematology/Oncology

Stanford Advisors

Lab Affiliations

Graduate and Fellowship Programs

  • Pediatric Hem/Onc (Fellowship Program)

All Publications

  • Biology of the bone marrow microenvironment and myelodysplastic syndromes MOLECULAR GENETICS AND METABOLISM Rankin, E. B., Narla, A., Park, J. K., Lin, S., Sakamoto, K. M. 2015; 116 (1-2): 24-28


    Myelodysplastic syndromes (MDS) are characterized by cytopenias resulting from ineffective hematopoiesis with a predisposition to transform to acute myeloid leukemia (AML). Recent evidence suggests that the hematopoietic stem cell microenvironment contributes to the pathogenesis of MDS. Inflammation and hypoxia within the bone marrow are key regulators of hematopoietic stem and progenitor cells that can lead to several bone marrow failure syndromes, including MDS. In this brief review, we provide an overview of the clinical and molecular features of MDS, the bone marrow microenvironment, and specific pathways that lead to abnormal blood cell development in MDS. Characterization of key steps in the pathogenesis of MDS will lead to new approaches to treat patients with this disease.

    View details for DOI 10.1016/j.ymgme.2015.07.004

    View details for Web of Science ID 000361423600004

  • Protein competition switches the function of COP9 from self-renewal to differentiation. Nature Pan, L., Wang, S., Lu, T., Weng, C., Song, X., Park, J. K., Sun, J., Yang, Z. H., Yu, J., Tang, H., McKearin, D. M., Chamovitz, D. A., Ni, J., Xie, T. 2014


    The balance between stem cell self-renewal and differentiation is controlled by intrinsic factors and niche signals. In the Drosophila melanogaster ovary, some intrinsic factors promote germline stem cell (GSC) self-renewal, whereas others stimulate differentiation. However, it remains poorly understood how the balance between self-renewal and differentiation is controlled. Here we use D. melanogaster ovarian GSCs to demonstrate that the differentiation factor Bam controls the functional switch of the COP9 complex from self-renewal to differentiation via protein competition. The COP9 complex is composed of eight Csn subunits, Csn1-8, and removes Nedd8 modifications from target proteins. Genetic results indicated that the COP9 complex is required intrinsically for GSC self-renewal, whereas other Csn proteins, with the exception of Csn4, were also required for GSC progeny differentiation. Bam-mediated Csn4 sequestration from the COP9 complex via protein competition inactivated the self-renewing function of COP9 and allowed other Csn proteins to promote GSC differentiation. Therefore, this study reveals a protein-competition-based mechanism for controlling the balance between stem cell self-renewal and differentiation. Because numerous self-renewal factors are ubiquitously expressed throughout the stem cell lineage in various systems, protein competition may function as an important mechanism for controlling the self-renewal-to-differentiation switch.

    View details for DOI 10.1038/nature13562

    View details for PubMedID 25119050

  • The miRNA pathway intrinsically controls self-renewal of Drosophila germline stem cells CURRENT BIOLOGY Park, J. K., Liu, X., Strauss, T. J., McKearin, D. M., Liu, Q. 2007; 17 (6): 533-538


    Stem cells uniquely self-renew and maintain tissue homoeostasis by differentiating into different cell types to replace aged or damaged cells [1]. During oogenesis of Drosophila melanogaster, self-renewal of germline stem cells (GSCs) requires both intrinsic signaling mechanisms and extrinsic signals from neighboring niche cells [2]. Emerging evidence suggests that microRNA (miRNA)-mediated translational regulation may also control Drosophila GSC self-renewal [3, 4]. It is unclear, however, whether the miRNA pathway functions within stem cells or niche cells to maintain GSCs. In Drosophila, Dicer-1 (Dcr-1) and the double-stranded RNA binding protein Loquacious (Loqs) catalyze miRNA biogenesis [3-5]. Here, we generate loqs knockout (loqs(KO)) flies by ends-out homologous recombination and show that loqs is essential for embryonic viability and ovarian GSC maintenance. Both developmental and miRNA processing defects are rescued by transgenic expression of Loqs-PB, but not Loqs-PA. Furthermore, mosaic germline analysis indicates that Loqs is required intrinsically for GSC maintenance. Consistently, GSCs are restored in loqs mutant ovaries by germline expression, but not somatic expression, of Loqs-PB. Together, these results demonstrate that Loqs-PB, but not Loqs-PA, is necessary and sufficient for Drosophila development and the miRNA pathway. Our study strongly suggests that miRNAs play an intrinsic, but not extrinsic, role in Drosophila female GSC self-renewal.

    View details for DOI 10.1016/j.cub.2007.01.060

    View details for Web of Science ID 000245225500026

    View details for PubMedID 17320391

  • Bam and Bgcn antagonize Nanos-dependent germ-line stem cell maintenance PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Li, Y., Minor, N. T., Park, J. K., McKearin, D. M., Maines, J. Z. 2009; 106 (23): 9304-9309


    The balance between germ-line stem cell (GSC) self-renewal and differentiation in Drosophila ovaries is mediated by the antagonistic relationship between the Nanos (Nos)-Pumilio translational repressor complex, which promotes GSC self-renewal, and expression of Bam, a key differentiation factor. Here, we find that Bam and Nos proteins are expressed in reciprocal patterns in young germ cells. Repression of Nos in Bam-expressing cells depends on sequences in the nos 3'-UTR, suggesting that Nos is regulated by translational repression. Ectopic Bam causes differentiation of GSCs, and this activity depends on the endogenous nos 3'-UTR sequence. Previous evidence showed that Bgcn is an obligate factor for the ability of Bam to drive differentiation, and we now report that Bam forms a complex with Bgcn, a protein related to the RNA-interacting DExH-box polypeptides. Together, these observations suggest that Bam-Bgcn act together to antagonize Nos expression; thus, derepressing cystoblast-promoting factors. These findings emphasize the importance of translational repression in balancing stem cell self-renewal and differentiation.

    View details for DOI 10.1073/pnas.0901452106

    View details for Web of Science ID 000266817500037

    View details for PubMedID 19470484

  • Dicer-1, but not Loquacious, is critical for assembly of miRNA-induced silencing complexes RNA-A PUBLICATION OF THE RNA SOCIETY Liu, X., Park, J. K., Jiang, F., Liu, Y., Mckearin, D., Liu, Q. 2007; 13 (12): 2324-2329


    Double-stranded RNA-binding proteins (dsRBPs), such as R2D2 and Loquacious (Loqs), function in tandem with Dicer (Dcr) enzymes in RNA interference (RNAi). In Drosophila, Dcr-1/Loqs and Dcr-2/R2D2 complexes generate microRNAs (miRNAs) and small interfering RNAs (siRNAs), respectively. Although R2D2 does not regulate siRNA production, R2D2 and Dcr-2 coordinately bind siRNAs to promote assembly of the siRNA-induced silencing (siRISC) complexes. Conversely, Loqs enhances miRNA production. It is uncertain if Dcr-1 and Loqs facilitate miRNA loading onto the miRISC complexes. Here we used loqs knockout (KO) flies to characterize the physiological functions of Loqs in the miRNA pathway. Northern analysis revealed consistent accumulation of precursor (pre)-miRNAs in loqs(KO) flies. However, the lack of Loqs had differential effects on mature miRNAs: some are diminished, whereas others maintain wild-type levels. Importantly, the data suggest that miRNA production is not the rate-limiting step of the miRNA pathway. We show that Dcr-1, but not Loqs, is critical for assembly of miRISCs by using dcr-1 or loqs null egg extract. Consistent with this, recombinant Dcr-1 could efficiently interact with miRNA duplex in the absence of Loqs. Together, our results indicate that Loqs plays a prominent role in miRNA biogenesis, but is largely dispensable for miRISC assembly. Thus, Loqs and R2D2 represent two distinct functional modes for dsRBPs in the RNAi pathways.

    View details for DOI 10.1261/rna.723707

    View details for Web of Science ID 000250957700025

    View details for PubMedID 17928574

  • Stonewalling Drosophila stem cell differentiation by epigenetic controls DEVELOPMENT Maines, J. Z., Park, J. K., Williams, M., McKearin, D. M. 2007; 134 (8): 1471-1479


    During Drosophila oogenesis, germline stem cell (GSC) identity is maintained largely by preventing the expression of factors that promote differentiation. This is accomplished via the activity of several genes acting either in the GSC or in its niche. The translational repressors Nanos and Pumilio act in GSCs to prevent differentiation, probably by inhibiting the translation of early differentiation factors, whereas niche signals prevent differentiation by silencing transcription of the differentiation factor Bam. We have found that the DNA-associated protein Stonewall (Stwl) is also required for GSC maintenance. stwl is required cell-autonomously; clones of stwl(-) germ cells were lost by differentiation, and ectopic Stwl caused an expansion of GSCs. stwl mutants acted as Suppressors of variegation, indicating that stwl normally acts in chromatin-dependent gene repression. In contrast to several previously described GSC maintenance factors, Stwl probably functions epigenetically to prevent GSC differentiation. Stwl-dependent transcriptional repression does not target bam, but rather Stwl represses the expression of many genes, including those that may be targeted by Nanos and Pumilio translational inhibition.

    View details for DOI 10.1242/dev.02810

    View details for Web of Science ID 000245118300003

    View details for PubMedID 17344229

  • Phenotypic continuum in neuronopathic Gaucher disease: An intermediate phenotype between type 2 and type 3 JOURNAL OF PEDIATRICS Goker-Alpan, O., Schiffmann, R., Park, J. K., Stubblefield, B. K., Tayebi, N., Sidransky, E. 2003; 143 (2): 273-276


    Neuronopathic Gaucher disease, classically divided into two types, can have a continuum of phenotypes, often defying categorization. Nine children had an intermediate phenotype characterized by a delayed age of onset but rapidly progressive neurological disease, including refractory seizures and oculomotor abnormalities. There was genotypic heterogeneity among these patients.

    View details for DOI 10.1067/S0022-3476(03)00302-0

    View details for Web of Science ID 000185118300028

    View details for PubMedID 12970647

  • Reciprocal and nonreciprocal recombination at the glucocerebrosidase gene region: Implications for complexity in Gaucher disease AMERICAN JOURNAL OF HUMAN GENETICS Tayebi, N., Stubblefield, B. K., Park, J. K., Orvisky, E., Walker, J. M., LaMarca, M. E., Sidransky, E. 2003; 72 (3): 519-534


    Gaucher disease results from an autosomal recessive deficiency of the lysosomal enzyme glucocerebrosidase. The glucocerebrosidase gene is located in a gene-rich region of 1q21 that contains six genes and two pseudogenes within 75 kb. The presence of contiguous, highly homologous pseudogenes for both glucocerebrosidase and metaxin at the locus increases the likelihood of DNA rearrangements in this region. These recombinations can complicate genotyping in patients with Gaucher disease and contribute to the difficulty in interpreting genotype-phenotype correlations in this disorder. In the present study, DNA samples from 240 patients with Gaucher disease were examined using several complementary approaches to identify and characterize recombinant alleles, including direct sequencing, long-template polymerase chain reaction, polymorphic microsatellite repeats, and Southern blots. Among the 480 alleles studied, 59 recombinant alleles were identified, including 34 gene conversions, 18 fusions, and 7 downstream duplications. Twenty-two percent of the patients evaluated had at least one recombinant allele. Twenty-six recombinant alleles were found among 310 alleles from patients with type 1 disease, 18 among 74 alleles from patients with type 2 disease, and 15 among 96 alleles from patients with type 3 disease. Several patients carried two recombinations or mutations on the same allele. Generally, alleles resulting from nonreciprocal recombination (gene conversion) could be distinguished from those arising by reciprocal recombination (crossover and exchange), and the length of the converted sequence was determined. Homozygosity for a recombinant allele was associated with early lethality. Ten different sites of crossover and a shared pentamer motif sequence (CACCA) that could be a hotspot for recombination were identified. These findings contribute to a better understanding of genotype-phenotype relationships in Gaucher disease and may provide insights into the mechanisms of DNA rearrangement in other disorders.

    View details for Web of Science ID 000181152600002

    View details for PubMedID 12587096

  • Myoclonic epilepsy in Gaucher disease: genotype-phenotype insights from a rare patient subgroup PEDIATRIC RESEARCH Park, J. K., Orvisky, E., Tayebi, N., Kaneski, C., LaMarca, M. E., Stubblefield, B. K., Martin, B. M., Schiffmann, R., Sidransky, E. 2003; 53 (3): 387-395


    Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase, presents with a wide spectrum of manifestations. Although Gaucher disease has been divided into three clinical types, patients with atypical presentations continue to be recognized. A careful phenotypic and genotypic assessment of patients with unusual symptoms may help define factors that modify phenotype in this disorder. One such example is a rare subgroup of patients with type 3 Gaucher disease who develop progressive myoclonic epilepsy. We evaluated 16 patients with myoclonic epilepsy, nine of whom were diagnosed by age 4 y with severe visceral involvement and myoclonus, and seven with a more chronic course, who were studied between ages 22 and 40. All of the patients had abnormal horizontal saccadic eye movements. Fourteen different genotypes were encountered, yet there were several shared alleles, including V394L (seen on two alleles), G377S (seen on three alleles), and L444P, N188S, and recombinant alleles (each found on four alleles). V394L, G377S, and N188S are mutations that have previously been associated with non-neuronopathic Gaucher disease. The spectrum of genotypes differed significantly from other patients with type 3 Gaucher disease, where genotypes L444P/L444P and R463C/null allele predominated. Northern blot studies revealed a normal glucocerebrosidase transcript, whereas Western studies showed that the patients studied lacked the processed 56 kD isoform of the enzyme, consistent with neuronopathic Gaucher disease. Brain autopsy samples from two patients demonstrated elevated levels of glucosylsphingosine, a toxic glycolipid, which could contribute to the development of myoclonus. Thus, although there were certain shared mutant alleles found in these patients, both the lack of a shared genotype and the variability in clinical presentations suggest that other modifiers must contribute to this rare phenotype.

    View details for DOI 10.1203/01.PDR.0000049515.79882.94

    View details for Web of Science ID 000181143200005

    View details for PubMedID 12595585

  • Glucosylsphingosine accumulation in tissues from patients with Gaucher disease: correlation with phenotype and genotype MOLECULAR GENETICS AND METABOLISM Orvisky, E., Park, J. K., LaMarca, M. E., Ginns, E. I., Martin, B. M., Tayebi, N., Sidransky, E. 2002; 76 (4): 262-270


    Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase, presents with a wide spectrum of clinical manifestations including neuronopathic and non-neuronopathic forms. While the lipid glucosylceramide is stored in both patients with Gaucher disease and in a null allele mouse model of Gaucher disease, elevated levels of a second potentially toxic substrate, glucosylsphingosine, are also found. Using high performance liquid chromatography, glucosylsphingosine levels were measured in tissues from patients with type 1, 2, and 3 Gaucher disease. Glucosylsphingosine was measured in 16 spleen samples (8 type 1; 4 type 2; and 4, type 3) and levels ranged from 54 to 728 ng/mg protein in the patients with type 1 disease, 133 to 1200 ng/mg protein in the patients with type 2, and 109 to 1298 ng/mg protein in the type 3 samples. The levels of splenic glucosylsphingosine bore no relation to the type of Gaucher disease, the age of the patient, the genotype, nor the clinical course. In the same patients, hepatic glucosylsphingosine levels were lower than in spleen. Glucosylsphingosine was also measured in brains from 13 patients (1 type 1; 8 type 2; and 4 type 3). While the glucosylsphingosine level in the brain from the type 1 patient, 1.0 ng/mg protein, was in the normal range, the levels in the type 3 samples ranged from 14 to 32 ng/mg protein, and in the type 2 samples from 24 to 437 ng/mg protein, with the highest values detected in two fetuses with hydrops fetalis. The elevated levels found in brains from patients with neuronopathic Gaucher disease support the hypothesis that glucosylsphingosine may contribute to the nervous system involvement in these patients.

    View details for Web of Science ID 000178018200004

    View details for PubMedID 12208131

  • A deletion-insertion mutation in the phosphomannomutase 2 gene in an African American patient with congenital disorders of glycosylation-Ia AMERICAN JOURNAL OF MEDICAL GENETICS Tayebi, N., Andrews, D. Q., Park, J. K., Orvisky, E., McReynolds, J., Sidransky, E., Krasnewich, D. M. 2002; 108 (3): 241-246


    Congenital disorders of glycosylation (CDG) are a group of metabolic disorders with multisystemic involvement characterized by abnormalities in the synthesis of N-linked oligosaccharides. The most common form, CDG-Ia, resulting from mutations in the gene encoding the enzyme phosphomannomutase (PMM2), manifests with severe abnormalities in psychomotor development, dysmorphic features and visceral involvement. While this disorder is panethnic, we present the first cases of CDG-Ia identified in an African American family with two affected sisters. The proband had failure to thrive in infancy, hypotonia, ataxia, cerebellar hypoplasia and developmental delay. On examination, she also exhibited strabismus, inverted nipples and an atypical perineal fat distribution, all features characteristic of CDG-Ia. Direct sequencing demonstrated that the patient had a unique genotype, T237M/c.565-571 delAGAGAT insGTGGATTTCC. The novel deletion-insertion mutation, which was confirmed by subcloning and sequencing of each allele, introduces a stop codon 11 amino acids downstream from the site of the deletion. The presence of this deletion-insertion mutation at cDNA position 565 suggests that this site in the PMM2 gene may be a hotspot for chromosomal breakage.

    View details for DOI 10.1002/ajmg.10246

    View details for Web of Science ID 000174225900014

    View details for PubMedID 11891694

  • The E326K mutation and Gaucher disease: mutation or polymorphism? CLINICAL GENETICS Park, J. K., Tauebi, N., Stubblefield, B. K., LaMarca, M. E., MacKenzie, J. J., Stone, D. L., Sidransky, E. 2002; 61 (1): 32-34


    Gaucher disease is caused by mutations in the gene for human glucocerebrosidase, a lysosomal enzyme involved in the intracellular hydrolysis of glucosylceramide. While over 150 different glucocerebrosidase mutations have been identified in patients with Gaucher disease, not all reported mutations have been fully characterized as being causative. One such mutation is the E326K mutation, which results from a G to A nucleotide substitution at genomic position 6195 and has been identified in patients with type 1, type 2 and type 3 Gaucher disease. However, in each instance, the E326K mutation was found on the same allele with another glucocerebrosidase mutation. Utilizing polymerase chain reaction (PCR) screening and restriction digestions of both patients with Gaucher disease and normal controls, we identified the E326K allele in both groups. Of the 310 alleles screened from patients with Gaucher disease, the E326K mutation was detected in four alleles (1.3%). In addition, screening for the E326K mutation among normal controls from a random population revealed that three alleles among 316 screened (0.9%) also carried the E326K mutation. In the normal controls with the E326K allele, the glucocerebrosidase gene was completely sequenced, but no additional mutations were found. Because the E326K mutation may be a polymorphism, we caution that a careful examination of any allele with this mutation should be performed to check for the presence of other glucocerebrosidase mutations.

    View details for Web of Science ID 000174828700009

    View details for PubMedID 11903352

  • The Identification of Eight Novel Glucocerebrosidase (GBA) Mutations in Patients with Gaucher Disease HUMAN MUTATION Orvisky, E., Park, J. K., Parker, A., Walker, J. M., Martin, B. M., Stubblefield, B. K., Uyama, E., Tayebi, N., Sidransky, E. 2002; 19 (4)


    Mutations in the gene encoding for the lysosomal enzyme glucocerebrosidase (GBA) result in Gaucher disease. In this study, seven novel missense mutations in the glucocerebrosidase gene (A136E, H162P, K198E, Y205C, F251L, Q350X and I402F) and a splice site mutation (IVS10+2T-->A) were identified by direct sequencing of three amplified segments of the glucocerebrosidase gene. Five of the novel mutations were found in patients with neuronopathic forms of Gaucher disease, two of which, K198E and F251L, appear to be associated with type 2 Gaucher disease.

    View details for DOI 10.1002/humu.9024

    View details for Web of Science ID 000207901300002

    View details for PubMedID 11933202

  • Glucocerebrosidase mutations among African-American patients with type 1 Gaucher disease AMERICAN JOURNAL OF MEDICAL GENETICS Park, J. K., Koprivica, V., Andrews, D. Q., Madike, V., Tayebi, N., Stone, D. L., Sidransky, E. 2001; 99 (2): 147-151


    While the inherited deficiency of the enzyme glucocerebrosidase (Gaucher disease) is panethnic in its distribution, there have not been studies of the mutations encountered in specific ethnic groups in the United States, other than those on Ashkenazi Jews. We present the clinical descriptions and genotypes of seven patients of African-American ancestry with type 1 Gaucher disease, and summarize the published literature regarding the genotypes encountered in this population. All seven of the patients had moderate-to-severe manifestations of the disease, and all developed symptoms by adolescence. Genotypic analyses revealed that no two probands shared the same genotype. The common mutations N370S, c.84-85insG, IVS2+1 G-->A, and R463C were not seen. Mutation L444P was present on one allele in each of the patients; but the same mutation was encountered as a single point mutation in three of the patients, and as part of a recombinant allele in four of the patients. Southern blot analyses revealed a glucocerebrosidase fusion allele in one patient, and a duplication resulting from recombination in the region downstream from the glucocerebrosidase gene in three of the patients. Five different point mutations (A90T, R48W, N117D, R170C, and V352L), one deletion mutation (c.222-224 delTAC), and one insertion mutation (c.153-154 insTACAGC) were encountered. Our results demonstrate that there is significant genotypic heterogeneity among African-American patients with type 1 Gaucher disease, and that recombinations in the glucocerebrosidase gene locus are particularly common in this patient group. Published 2001 Wiley-Liss, Inc.

    View details for Web of Science ID 000167252200012

    View details for PubMedID 11241475

  • Gene rearrangement on 1q21 introducing a duplication of the glucocerebrosidase pseudogene and a metaxin fusion gene HUMAN GENETICS Tayebi, N., Park, J., Madike, V., Sidransky, E. 2000; 107 (4): 400-403


    The genes for glucocerebrosidase and metaxin, both located on chromosome 1q21, each have a highly homologous pseudogene sequence nearby. We describe a novel recombinant allele consisting of a duplication of the glucocerebrosidase pseudogene and a fusion between the metaxin gene and its pseudogene, resulting from a crossover between metaxin and pseudometaxin in the region downstream of the glucocerebrosidase gene. We also show that certain individuals have a metaxin-pseudometaxin fusion gene without a duplication, resulting from the same crossover. DNA from patients with Gaucher disease and normal controls were screened for recombinant alleles by Southern blot analyses prepared with the restriction enzymes SspI and HincII and by direct sequencing. Downstream alterations were identified in eight of the 398 patient alleles studied and in seven of the 200 normal control alleles examined, and were encountered more frequently among patients and controls of African-American ancestry. This is the first recognition of a duplicated allele in the glucocerebrosidase gene region, and its presence may contribute to genotype-phenotype studies in Gaucher disease.

    View details for Web of Science ID 000165419300016

    View details for PubMedID 11129343

  • Analysis and classification of 304 mutant alleles in patients with type 1 and type 3 Gaucher disease AMERICAN JOURNAL OF HUMAN GENETICS Koprivica, V., Stone, D. L., Park, J. K., Callahan, M., Frisch, A., Cohen, I. J., Tayebi, N., Sidransky, E. 2000; 66 (6): 1777-1786


    Gaucher disease results from the inherited deficiency of the enzyme glucocerebrosidase (EC Although >100 mutations in the gene for human glucocerebrosidase have been described, most genotype-phenotype studies have focused upon screening for a few common mutations. In this study, we used several approaches-including direct sequencing, Southern blotting, long-template PCR, restriction digestions, and the amplification refraction mutation system (ARMS)-to genotype 128 patients with type 1 Gaucher disease (64 of Ashkenazi Jewish ancestry and 64 of non-Jewish extraction) and 24 patients with type 3 Gaucher disease. More than 97% of the mutant alleles were identified. Fourteen novel mutations (A90T, N117D, T134I, Y135X, R170C, W184R, A190T, Y304X, A341T, D399Y, c.153-154insTACAGC, c.203-204insC, c.222-224delTAC, and c.1122-1123insTG) and many rare mutations were detected. Recombinant alleles were found in 19% of the patients. Although 93% of the mutant alleles in our Ashkenazi Jewish type 1 patients were N370S, c.84-85insG, IVS2+1G-->A or L444P, these four mutations accounted for only 49% of mutant alleles in the non-Jewish type 1 patients. Genotype-phenotype correlations were attempted. Homozygosity or heterozygosity for N370S resulted in type 1 Gaucher disease, whereas homozygosity for L444P was associated with type 3. Genotype L444P/recombinant allele resulted in type 2 Gaucher disease, and homozygosity for a recombinant allele was associated with perinatal lethal disease. The phenotypic consequences of other mutations, particularly R463C, were more inconsistent. Our results demonstrate a high rate of mutation detection, a large number of novel and rare mutations, and an accurate assessment of the prevalence of recombinant alleles. Although some genotype-phenotype correlations do exist, other genetic and environmental factors must also contribute to the phenotypes encountered, and we caution against relying solely upon genotype for prognostic or therapeutic judgements.

    View details for Web of Science ID 000088373800006

    View details for PubMedID 10796875