Pragna I Patel

University of Southern California | USC · Institute for Genetic Medicine

Novel mutations in myelin and myelin-associated genes have provided important information on oligodendrocytes and myelin and the effects of their disruption on the normal developmental process of myelination of the central nervous system (CNS). We report here a mutation in the folliculin-interacting protein 2 (FNIP2) gene in the Weimaraner dog that...

Charcot-Marie-Tooth disease type 1A (CMT1A) is a dominantly inherited, slowly progressive, often-disabling symmetrical distal sensorimotor polyneuropathy, caused by duplication of 1.5 Mb on the short arm of chromosome 17 with consequent trisomy for PMP22 (peripheral myelin protein 22) encoding a peripheral nervous system myelin protein, that affect...

Congenital diaphragmatic hernia (CDH) is a common life-threatening birth defect. Recessive mutations in the FRAS1-related extracellular matrix 1 (FREM1) gene have been shown to cause Bifid Nose with or without Anorectal and Renal anomalies (BNAR) syndrome and Manitoba OculoTrichoAnal (MOTA) syndrome, but have not been previously implicated in the d...

Recent studies have examined the influence on patterns of human genetic variation of a variety of cultural practices. In India, centuries-old marriage customs have introduced extensive social structuring into the contemporary population, potentially with significant consequences for genetic variation. Social stratification in India is evident as so...

Schematic of the F critical region. (A) The region within the chicken linkage group E22C19W28_E50C23 harbouring the F mutation in the KRT75 gene. (adapted from the Ensembl genome browser http://www.ensembl.org/). (B) The F mutation was determined to be an 84-bp deletion covering the junction of exon 5 and intron 5 in the KRT75 gene and is indicated...

KRT75 genotypes of parental chickens and progenies in the experimental cross. These results were obtained with DNA samples used for the genome-scan and those that were not included in the genome scan P. (A) Lab IDs, phenotypes and lane number for samples used in the genome-scan. (B) KRT75 genotypes of samples used in the genome scan. Samples 33 and...

Natural bending of feathers from both sides of a chicken. (A) Images of flight feathers from opposite sides of the same normal chicken (the R8 and L8 denote the 8th feather taken from the right and left wing, respectively). (B) The trend of curves (s) shows reflective symmetry. (TIF)

Sequence variants within the linkage group chrE22C19W28_E50C23. (PDF)

Detailed PCNA and TUNEL staining in the rachis of normal and frizzle chicken regenerated body feathers at different levels. (A) Diagram of a 30 day regenerating follicle. Levels I, II and III show the planes of section, from immature to mature regions of a feather follicle. (B, C) Comparison of PCNA staining between normal (B) and frizzle (C) feath...

KRT75 is expressed in the frizzle feather follicles. Lanes 1–3 show the [72], [73]PCR products amplified from total cDNA prepared using a poly-T oligonucleotide primer, whereas lanes 4–6 show the PCR products amplified from total cDNA prepared using random hexamer primers. Lanes 1 and 4 show the PCR products amplified using primers located in the 5...

Multiple sequence alignment of amniote K75 proteins. The alignment was prepared using MUSCLE implemented in the CLC Bio 6.0 (Aarhus, Denmark). The sequences were translated from AY574985.1 (red junglefowl), XM_003205996 (turkey), XM_002194971 (zebrafinch KRT6A), XM_002194995 (zebrafinch KRT75), XM_003216971 (lizard), XM_001362788 (opossum), XM_0015...

Detailed H&E and TUNEL staining at different levels among control, RCAS-KRT75-WT and RCAS-KRT75-MT mis-expression samples. (A) Diagram showing levels for section from immature (level I) to mature (level IV) regions of an E13 embryonic body feather. (B–D′) H&E and TUNEL staining at different levels. (B) and (B′) control; (C) and (C′) RCAS-KRT75-WT;...

The summary of KRT75 genotypes of the parents and progenies in the experimental cross. Lane 1 shows the genotype of the heterozygous father (+/F), lane 2 shows the genotype of wild-type mother, lane 3 shows the genotype of frizzle offsprings, lane 4 show the genotype of normal offspring (I do not think we need delete this) (TIF)

Domains of K75. The yellow-line box highlights the deletion which removes the entire part of link L2 and some parts of the coiled-coil segments of 2A and 2B. The domain information was obtained from the Human Intermediate Filament Mutation Database (www.interfil.org). (TIF)

Contrast between feathers that have misexpressed GFP and overexpressed KRT75-WT. (A) Comparison of the feathers with misexpressed GFP (Control) and KRT75-WT. (B) Effects of the viral misexpression, as shown by the qualitative change of the curves of θ(s). (TIF)

Primers designed to screen for the causative mutation in the candidate gene regions. (PDF)

Feathers have complex forms and are an excellent model to study the development and evolution of morphologies. Existing chicken feather mutants are especially useful for identifying genetic determinants of feather formation. This study focused on the gene F, underlying the frizzle feather trait that has a characteristic curled feather rachis and ba...

X-linked congenital generalized hypertrichosis (CGH), an extremely rare condition characterized by universal overgrowth of terminal hair, was first mapped to chromosome Xq24-q27.1 in a Mexican family. However, the underlying genetic defect remains unknown. We ascertained a large Chinese family with an X-linked congenital hypertrichosis syndrome com...

Mendoza-Fandino GA, Gee JM, Ben-Dor S, Gonzalez-Quevedo C, Lee K, Kobayashi Y, Hartiala J, Myers RM, Leal SM, Allayee H, Patel PI. A novel g.-1258G>A mutation in a conserved putative regulatory element of PAX9 is associated with autosomal dominant molar hypodontia. Mutations in the transcription factor PAX9 which plays a critical role in the switch...

Congenital absence of teeth is a complex condition affecting several parameters of oral development. This is the first study to measure tooth crown dimensions using image analysis in a family with hypodontia in whom the mutation has been identified, and compare them with a control group. Study models were obtained from 10 family members from three...

When performing association studies in populations that have not been the focus of large-scale investigations of haplotype variation, it is often helpful to rely on genomic databases in other populations for study design and analysis - such as in the selection of tag SNPs and in the imputation of missing genotypes. One way of improving the use of t...

Supplementary Tables 4–20. Allele frequencies of the 17 SNPs in other worldwide populations.

Supplementary Tables 1–3. Genotype frequencies of the 17 SNPs (Table S1), and the ALOX5P (Table S2) and DG8S737 (Table S3) microsatellites.

Asian Indians display a high prevalence of diseases linked to changes in diet and environment that have arisen as their lifestyle has become more westernized. Using 1200 genome-wide polymorphisms in 432 individuals from 15 Indian language groups, we have recently shown that: (i) Indians constitute a distinct population-genetic cluster, and (ii) des...

To identify genes heretofore undiscovered as critical players in the biogenesis of teeth, we have used microarray gene expression analysis of the developing mouse molar tooth (DMT) between postnatal day (P) 1 and P10 to identify genes differentially expressed when compared with 16 control tissues. Of the top 100 genes exhibiting increased expressio...

Smith-Magenis syndrome (SMS) is a multisystem disorder characterized by developmental delay and mental retardation, a distinctive behavioral phenotype, and sleep disturbance. We undertook a comprehensive meta-analysis to identify genotype-phenotype relationships to further understand the clinical variability and genetic factors involved in SMS. Cli...

Inherited dental anomalies such as hypodontia, supernumerary teeth, enamel defects, and diastema are evident in large segments of most populations. Although treatment options for many of these conditions are ever improving, much remains to be understood about their etiology and pathophysiology. In this review, the authors hope to enthuse dental pro...

After clinical laboratory tests have been performed, it can be difficult to obtain DNA without further patient involvement. Although the blood clot remaining within the serum-separation tube after serum collection is a source of DNA, recovery of the clot from the tube is a significant challenge. We devised a method to efficiently remove clotted blo...

Amelogenesis imperfecta (AI) is a collective term used to describe phenotypically diverse forms of defective tooth enamel development. AI has been reported to exhibit a variety of inheritance patterns, and several loci have been identified that are associated with AI. We have performed a genome-wide scan in a large Brazilian family segregating an a...

Ongoing modernization in India has elevated the prevalence of many complex genetic diseases associated with a western lifestyle and diet to near-epidemic proportions. However, although India comprises more than one sixth of the world's human population, it has largely been omitted from genomic surveys that provide the backdrop for association studi...

Latitudes and Longitudes Used for the Samples from India (8 KB PDF)

Pairwise Values of Fst for Indian Populations (12 KB PDF)

Amount by Which Allele Sizes Were Translated to Make the HGDP-CEPH and Indian Microsatellite Data Comparable (21 KB PDF)

Thousands of inherited human disorders have been catalogued to date, but the underlying genetic causes of less than 20 percent of those disorders have been discovered. TYPE OF STUDIES REVIEWED: The completion of the Human Genome Project (HGP) has made available the DNA sequence of all 24 human chromosomes, thereby allowing the localization of all h...

Despite numerous advances made in identifying the genes for rare mendelian forms of cardiovascular disease (CVD), relatively little is known about the common, complex forms at the genetic level. Moreover, most genes that have been associated with CVD, whether they are single gene forms or more common forms of the disease, have primarily been involv...

We and others have identified several hundred ancestry informative markers (AIMs) with large allele frequency differences between different major ancestral groups. For this study, a panel of 199 widely distributed AIMs was used to examine a diverse set of 796 DNA samples including self-identified European Americans, West Africans, East Asians, Amer...

Congenitally missing teeth, or hypodontia, is one of the most common abnormalities of the human dentition and has a critical and often lifelong impact on the oral health of affected individuals. Here we review hypodontia and describe the patterns of inheritance it can display. A short review of tooth development and a primer in human genetics are p...

Tooth development is a complex process of reciprocal interactions that we have only recently begun to understand. With the large number of genes involved in the odontogenic process, the opportunity for mutations to disrupt this process is high. Tooth agenesis (hypodontia) is the most common craniofacial malformation with patients missing anywhere f...

The term “genomic disorders” refers to a group of human genetic diseases caused by chromosome rearrangements, including deletions, duplications, and inversions (Lupski 1998, 2003). Susceptibility to these DNA rearrangements reflects genome architecture (Inoue and Lupski 2002; Stankiewicz and Lupski 2002a, 2002b). In many genomic disorders, the rear...

We describe the molecular analysis of three families with hypodontia involving primarily molar teeth and report two novel mutational mechanisms. Linkage analysis of two large families revealed that the hypodontia was linked to the PAX9 locus. These two families revealed missense mutations consisting of a glutamic acid substitution for lysine and a...

Primary and immortalized cultured Schwann cells are commonly utilized in analyses of myelin gene promoters, but few lines are well-characterized in terms of their endogenous expression of myelin genes. This is particularly significant in that cultured Schwann cells typically do not express myelin genes at levels comparable to those observed in vivo...

We recently identified a frame-shift mutation in the PAX9 gene as the underlying cause for hypodontia involving permanent molar teeth segregating in an autosomal dominant pattern in a single large family (Stockton et al. 2000). Here we report a small nuclear family in which a father and his daughter are affected with severe hypodontia, involving ag...

Smith-Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation syndrome associated with an interstitial deletion of chromosome 17 involving band p11.2. SMS is hypothesised to be a contiguous gene syndrome in which the phenotype arises from the haploinsufficiency of multiple, functionally-unrelated genes in close physical proximi...

Over- and under expression of the 22 kDa peripheral myelin protein (PMP22) results in dysmyelinating peripheral neuropathies, such as Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy, with the liability to pressure palsies (HNPP). Expression of the PMP22 gene is driven by two alternative promoters, P1 and P2, with transcripts o...

Overexpression of the 22-kDa peripheral myelin protein (PMP22) causes the inherited peripheral neuropathy, Charcot-Marie-Tooth disease type 1A (CMT1A). In an attempt to alter PMP22 gene expression as a possible therapeutic strategy for CMT1A, antiparallel triplex-forming oligonucleotides (TFO) were designed to bind to purine-rich target sequences i...

Friedreich ataxia (FRDA [MIM 229300]), the most prevalent inherited ataxia, is an autosomal recessive disease with onset in early childhood followed by an unremitting course that terminates with death in the fourth or fifth decade of life. It occurs at a frequency of 1–2 per 50,000 individuals. FRDA is characterized clinically by progressive gait a...

Dentinogenesis imperfecta (DGI) is characterized by discolored teeth with an opalescent sheen and dentin that fails to support enamel, causing it to easily chip. Two new studies show that DGI is associated with mutations in DSPP, a gene encoding dentin sialophosphoprotein that is processed into two proteins: dentin sialoprotein (DSP) and dentin pho...

Frataxin is a nuclear-encoded mitochondrial protein widely conserved among eukaryotes. Human frataxin (fxn) is severely reduced in Friedreich ataxia (FRDA), a frequent autosomal recessive neuro- and cardio-degenerative disease. Whereas the function of fxn is unknown, the yeast frataxin homolog (Yfh1p) has been shown to be involved in mitochondrial...

A frameshift mutation recently identified within the paired domain of the transcription factor, PAX9, has been linked to a unique form of oligodontia in a single, multigenerational family (Stockton et al., 2000). We now describe the phenotypic and segregation analyses of this remarkable kindred, the initial approach taken to identify a candidate ge...

To better understand the mechanism by which glucocorticosteroids (GLUC) could enhance myelination in the PNS, cultured rat Schwann cells were transiently transfected with reporter constructs in which luciferase expression was controlled by the promoter region of either the peripheral myelin protein-22 (PMP22) or the protein zero (P0) genes. GLUC st...

Most patients with Friedreich ataxia (FRDA) have abnormal GAA triplet repeat expansions in both X25 genes. The size of the GAA expansion in the shorter of the 2 expanded alleles correlates significantly with parameters of clinical severity and is inversely related to the age at onset. To describe the clinical and molecular genetic findings in a pat...

The vast majority of Friedreich ataxia patients are homozygous for large GAA triplet repeat expansions in intron 1 of the X25 gene. Instability of the expanded GAA repeat was examined in 23 chromosomes bearing 97–1250 triplets in lymphoblastoid cell lines passaged 20–39 times. Southern analyses revealed 18 events of significant changes in length ra...

We identified a frameshift mutation in the paired domain of PAX9 following genome-wide analysis of a family segregating autosomal dominant oligodontia. Affected members have normal primary dentition but lacked most permanent molars.

Smith-Magenis syndrome (SMS) is a multiple congenital anomaly/mental retardation syndrome associated with an interstitial deletion of chromosome band 17p11.2. The critical region is extremely gene-rich and spans approximately 1.5-2.0 Mb of DNA. Here we report the localization and partial characterization of the gene for subunit 3 of the COP9 signal...

Expressed sequence tag information was used to clone the full-length sequence for a new human lipoxygenase from the B cell line CCL-156. A related mouse sequence with 83% nucleotide identity to the human sequence was also cloned. The human lipoxygenase, when expressed via the baculovirus/insect cell system produced an ≈80-kDa protein capable of met...

In this Journal, we previously reported genetic linkage between loci on chromosome (chr)2p(ETM) and dominantly inherited essential tremor (ET) in a large American kindred of Czech ancestry. Other investigators reported another ET susceptibility locus on chr 3q (FET1) which accounted for over half of the Icelandic families that were studied. We now...

To map the gene causing an unusual EEG pattern of delta bursts that appears to segregate as an autosomal dominant trait in an Italian family. The EEG pattern was observed in four family members affected by idiopathic generalized epilepsy (IGE) and in six other clinically unaffected members. All available family members underwent clinical and EEG ex...

We analysed the nerve specific promoter of the peripheral myelin protein 22 gene (PMP22) in a set of 15 unrelated patients with Charcot-Marie-Tooth type 1 disease (CMT1) and 16 unrelated patients with hereditary neuropathy with liability to pressure palsies (HNPP). In these patients no duplication/deletion nor a mutation in the coding region of the...

To the Editor:In our recent article in the Journal (Yang et al. 1997xMolecular analysis of deletion (17)(p11.2p11.2) in a family segregating a 17p paracentric inversion: implications for carriers of paracentric inversions. Yang, SP, Bidichandani, SI, Figuera, LE, Juyal, RC, Saxon, PJ, Baldini, A, and Patel, PI. Am J Hum Genet. 1997; 60: 1184–1193Pu...

We report on a de novo intrachromosomal rearrangement of chromosome 17 in a patient with Smith-Magenis syndrome (SMS). This 11-year-old boy had short stature, midfacial hypoplasia, and behavioral problems characteristic of this syndrome. Cytogenetic analysis showed that the proximal long arm of a chromosome 17 (q11.2-q21.3) was inserted into its sh...

We report on a de novo intrachromosomal rearrangement of chromosome 17 in a patient with Smith-Magenis syndrome (SMS). This 11-year-old boy had short stature, mid-facial hypoplasia, and behavioral problems characteristic of this syndrome. Cytogenetic analysis showed that the proximal long arm of a chromosome 17 (q11.2-q21.3) was inserted into its s...

Friedreich ataxia (FRDA) is an autosomal recessive, neurodegenerative disease, characterized by progressive gait and limb ataxia, dysarthria, lower-limb areflexia, Babinski sign, loss of position and vibration senses, cardiomyopathy, and carbohydrate intolerance. It is the most common inherited ataxia, and is associated with a GAA triplet repeat ex...

A human "epidermal-type" 12-lipoxygenase (e-12LO) pseudogene was cloned using a murine e-12LO cDNA probe. Similar to other lipoxygenase genes, the genomic sequence revealed 14 exons and 13 introns covering 6.7 kb of DNA. cDNA corresponding to this gene was amplified from RNA of human skin and hair follicles by RACE-PCR and displayed 65-80% identity...

Friedreich ataxia (FRDA), an autosomal recessive, neurodegenerative disease is the most common inherited ataxia. The vast majority of patients are homozygous for an abnormal expansion of a polymorphic GAA triplet repeat in the first intron of the X25 gene, which encodes a mitochondrial protein, frataxin. Cellular degeneration in FRDA may be caused...

Smith-Magenis syndrome (SMS) is caused by an interstitial deletion of chromosome band 17p11.2 averaging 4–5 Mb. This deletion is likely to contain a large number of genes, each of which could potentially contribute toward the clinical phenotype. We report that the gene for topoisomerase III (hTOP3) is commonly deleted in SMS patients and maps betwe...

DNA is the chemical basis of heredity. Within its sequence is the information necessary for cells to live, grow, differentiate, and replicate. It is the DNA that provides both consistency (all humans generally look the same) and variability (height, eye, and hair color) among organisms. While the human genome is extremely polymorphic and the majori...

A male child with multiple congenital anomalies initially was clinically diagnosed as having Smith-Lemli-Opitz syndrome (SLOS). Subsequent cytogenetic studies revealed an interstitial deletion of 17p11.2, which is associated with Smith-Magenis syndrome (SMS). Biochemical studies were not supportive of a diagnosis of SLOS, and the child did not disp...

Ataxia-telangiectasia (A-T) is a recessive human disease characterized by radiation sensitivity, genetic instability, immunodeficiency, and high cancer risk. We previously used expression cloning to identify CAT4.5, a human cDNA that partially suppresses multiple aspects of the A-T phenotype upon transfection into cultured cells. Sequencing CAT4.5...

To describe 4 large families with essential tremor (ET) to draw attention to the marked clinical heterogeneity of ET. To use computer simulation analysis to provide information about the power of the family material for future linkage studies. We examined a total of 251 members from 4 kindreds with ET. The mean (+/-SD) age at onset of ET varied amo...

Smith-Magenis syndrome (SMS) comprises a complex physical and behavioral phenotype that is associated with an interstitial deletion of chromosome 17p11.2. The deletions observed in patients can range from <2 to >9 megabases of DNA and may include more than 100 genes. In order to determine the critical deletion interval responsible for the syndrome...

We have used bivariate flow karyotyping to quantify the deletions involving chromosome 17 in sixteen patients with Smith-Magenis syndrome (SMS). The fluorescence intensities of mitotic chromosomes stained with Hoechst 33258 and chromomycin were quantified in a dual-beam flow cytometer. For each patient, the position of the peak representing the del...

Smith-Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation syndrome associated with deletion of band p11.2 of chromosome 17. The deletion is typically detected by high-resolution cytogenetic analysis of chromosomes from peripheral lymphocytes. Fluorescence in situ hybridization (FISH) has been previously used to rule out app...

Using a case-control design, an association of schizophrenia with the dopamine D3 receptor gene (D3RG) locus was investigated. Initial analysis of pooled results from published studies revealed a significant excess of individuals homozygous for either allele among the patients. The association was next tested in two cohorts ascertained independentl...

The hypoxanthine phosphoribosyltransferase (HPRT) locus is a constitutively expressed housekeeping gene characterized by a notably higher level of expression in the mammalian brain. The enzyme it encodes is key to purine salvage in humans and is the basis for the X-linked recessive disorder, Lesch-Nyhan syndrome (LNS). Methylation in the promoter p...

Smith-Magenis syndrome (SMS) is a clinically recognizable, multiple congenital anomalies/mental retardation syndrome caused by an interstitial deletion involving band p11.2 of chromosome 17. Toward the molecular definition of the interval defining this microdeletion syndrome, 62 unrelated SMS patients in conjunction with 70 available unaffected par...

Friedreich's ataxia (FRDA) is an autosomal recessive, degenerative disease that involves the central and peripheral nervous systems and the heart. A gene, X25, was identified in the critical region for the FRDA locus on chromosome 9q13. The gene encodes a 210-amino acid protein, frataxin, that has homologs in distant species such as Caenorhabditis...

Folate-dependent one-carbon metabolism is critical for the synthesis of numerous cellular constituents required for cell growth, and serine hydroxymethyltransferase (SHMT) is central to this process. Our studies reveal that the gene for cytosolic SHMT (cSHMT) maps to the critical interval for Smith-Magenis syndrome (SMS) on chromosome 17p11.2. The...

The enzyme hypoxanthine phosphoribosyltransferase (HPRT), expressed at low levels in non-neuronal tissues and higher levels in the brain, catalyzes the cellular salvage of the purine bases hypoxanthine and guanine. A complete deficiency of HPRT results in Lesch-Nyhan syndrome (LNS). LNS is characterized by movement deficits, including chorea, dysto...

By analysis of crossovers in key recombinant families and by homozygosity analysis of inbred families, the Friedreich ataxia (FRDA) locus was localized in a 300-kb interval between the X104 gene and the microsatellite marker FR8 (D9S888). By homology searches of the sequence databases, we identified X104 as the human tight junction protein ZO-2 gen...

The hypoxanthine phosphoribosyltransferase (HPRT) gene is constitutively expressed at low levels in all tissues but at higher levels in the brain; the significance and mechanism of this differential expression are unknown. We previously identified a 182-bp element (hHPRT-NE) within the 5'-flanking region of the human HPRT (hHPRT) gene, which is inv...

Smith-Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation syndrome typically associated with a deletion of band p11.2 of human chromosome 17. Finucane et al. reported a 14-year-old boy with mild physical and behavior manifestations of SMS. No evidence for deletion was initially evident in 20 peripheral blood lymphocytes exa...

Idiopathic generalized epilepsy (IGE) is characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Twin and family studies suggest that genetic factors play a key part in IGE. A multilocus model appears to best fit the observed inheritance patterns. Mapping of IGE-related genes has be...