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1.  Familial hypertrophic cardiomyopathy owing to double heterozygosity for a 403Arg→ Trp mutation in exon 13 of the MYH7 gene and a novel mutation, 453Arg→ His, in exon 14 of the MYH7 gene: A case report 
An unusual clinical history of a 23-year-old male proband with obstructive hypertrophic cardiomyopathy associated with a rare genotype is presented. Genetic analysis of the proband found evidence for two distinct mutations of the MYH7 gene (the gene coding for the beta-myosin heavy chain): 403Arg→ Trp in exon 13 and a novel mutation, 453Arg→ His, in exon 14. A heterozygous site mutation was identified in exon 13 in the proband’s father but no mutation site was found in his mother. Thus, the novel mutation in exon 14 is a de novo mutation.
PMCID: PMC2859004  PMID: 20428263
Beta-myosin heavy chain; Genetic mutations; Hypertrophic cardiomyopathy; MYH7 gene
2.  MYH-9 Related Platelet Disorders: Strategies for Management and Diagnosis 
MYH-9 related platelet disorders belong to the group of inherited giant platelet disorders. The MYH-9 gene encodes the non-muscular myosin heavy chain IIA (NMMHCIIA), a cytoskeletal contractile protein. Several mutations in the MYH-9 gene lead to macrothrombocytopenia, and cytoplasmic inclusion bodies within leukocytes, while the number of megakaryocytes in the bone marrow is normal. Four overlapping syndromes, known as May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome and Sebastian platelet syndrome, describe different clinical manifestations of MYH9 gene mutations. Macrothrombocytopenia is present in all affected individuals, whereas only some develop additional clinical manifestations such as renal failure, hearing loss and presenile cataracts. The bleeding tendency is usually moderate, with menorrhagia and easy bruising being most frequent. The biggest risk for the individual is inappropriate treatment due to misdiagnosis of chronic autoimmune thrombocytopenia. More than 30 mutations within the 40 exons of the MYH-9 gene leading to macrothrombocytopenia have been identified, of which the upstream mutations up to amino acid ~1400 are more likely associated with syndromic manifestations than the downstream mutations. Diagnosis is based on identification of the granulocyte inclusion bodies using blood smears and immunofluorescence and is finally confirmed by identifying the mutation. Treatment is supportive and should be aimed to prevent iron deficiency anemia. Beside renal failure, the biggest risk for patients affected by a MYH-9 disorder are the adverse effects resulting form treatment based on the misdiagnosis of immune thrombocytopenia.
PMCID: PMC2980510  PMID: 21113248
MYH9 gene; Non-musclular myosin IIA; May-Hegglin anomaly; Epstein syndrome; Fechtner syndrome; Sebastian platelet syndrome; Macrothrombocytopenia
3.  Transfection of the mutant MYH9 cDNA reproduces the most typical cellular phenotype of MYH9-related disease in different cell lines 
PathoGenetics  2008;1:5.
Heterozygous mutations of MYH9, encoding the Non-Muscular Myosin Heavy Chain-IIA (NMMHC-IIA), cause a complex disorder named MYH9-related disease, characterized by a combination of different phenotypic features. At birth, patients present platelet macrocytosis, thrombocytopenia and leukocyte inclusions containing NMMHC-IIA. Moreover, later in life some of them develop the additional features of sensorineural hearing loss, cataracts and/or glomerulonephritis that sometimes leads to end stage renal failure.
To clarify the mechanism by which the mutant NMMHC-IIA could cause phenotypic anomalies at the cellular level, we examined the effect of transfection of the full-length mutated D1424H MYH9 cDNAs. We have observed, by confocal microscopy, abnormal distribution of the protein and formation of rod-like aggregates reminiscent of the leukocyte inclusions found in patients. Co-transfection of differently labeled wild-type and mutant full-length cDNAs showed the simultaneous presence of both forms of the protein in the intracellular aggregates.
These findings suggest that the NMMHC-IIA mutated in position 1424 is able to interact with the WT form in living cells, despite part of the mutant protein precipitates in non-functional aggregates. Transfection of the entire WT or mutant MYH9 in cell lines represents a powerful experimental model to investigate consequences of MYH9 mutations.
PMCID: PMC2633265  PMID: 19046415
4.  May Hegglin Anomaly: Rare Entity with Review of Literature 
We present a brief review of a rare entity, May Hegglin anomaly. We also put forth a few pictures characterizing it.
PMCID: PMC3311968  PMID: 23450942
5.  Transient neonatal diabetes mellitus caused by a de novo ABCC8 gene mutation 
Korean Journal of Pediatrics  2011;54(4):179-182.
Transient neonatal diabetes mellitus (TNDM) is a rare form of diabetes mellitus that presents within the first 6 months of life with remission in infancy or early childhood. TNDM is mainly caused by anomalies in the imprinted region on chromosome 6q24; however, recently, mutations in the ABCC8 gene, which encodes sulfonylurea receptor 1 (SUR1), have also been implicated in TNDM. Herein, we present the case of a male child with TNDM whose mutational analysis revealed a heterozygous c.3547C>T substitution in the ABCC8 gene, leading to an Arg1183Trp mutation in the SUR1 protein. The parents were clinically unaffected and did not show a mutation in the ABCC8 gene. This is the first case of a de novo ABCC8 gene mutation in a Korean patient with TNDM. The patient was initially treated with insulin and successfully switched to sulfonylurea therapy at 14 months of age. Remission of diabetes had occurred at the age of 16 months. Currently, the patient is 21 months old and is euglycemic without any insulin or oral hypoglycemic agents. His growth and physical development are normal, and there are no delays in achieving neurological and developmental milestones.
PMCID: PMC3127153  PMID: 21738553
Diabetes mellitus; Infant; Sulfonylurea receptor; Mutation
6.  First description of germline mosaicism in familial hypertrophic cardiomyopathy 
Journal of Medical Genetics  2000;37(2):132-134.
Familial hypertrophic cardiomyopathy is a genetically and phenotypically heterogeneous disease caused by mutations in seven sarcomeric protein genes. It is known to be transmitted as an autosomal dominant trait with rare de novo mutations.
A French family in which two members are affected by hypertrophic cardiomyopathy was clinically screened with electrocardiography and echocardiography. Genetic analyses were performed on leucocyte DNA by haplotype analysis with microsatellite markers at the MYH7 locus and mutation screening by single strand conformation polymorphism analysis. Two subjects exhibited severe hypertrophic cardiomyopathy. A mutation in the MYH7 gene was found in exon 14 (Arg453Cys). The two affected patients were carriers of the mutation, which was not found in the circulating lymphocytes of their parents. Haplotype analysis at the MYH7 locus with two intragenic microsatellite markers (MYOI and MYOII) and the absence of the mutation in the father's sperm DNA suggested that the mutation had been inherited from the mother. However, it was not found in either her fibroblasts or hair.
This is the first description of germline mosaicism shown by molecular genetic analysis in an autosomal dominant disorder and more especially in hypertrophic cardiomyopathy. This mosaicism had been inherited from the mother but did not affect her somatic cells. Such a phenomenon might account for some de novo mutations in familial hypertrophic cardiomyopathy.

Keywords: hypertrophic cardiomyopathy; germline mosaicism; β myosin heavy chain; genetics
PMCID: PMC1734529  PMID: 10662815
7.  MYH9-related disease: Five novel mutations expanding the spectrum of causative mutations and confirming genotype/phenotype correlations 
MYH9-related disease (MYH9-RD) is a rare autosomal dominant syndromic disorder caused by mutations in MYH9, the gene encoding for the heavy chain of non-muscle myosin IIA (myosin-9). MYH9-RD is characterized by congenital macrothrombocytopenia and typical inclusion bodies in neutrophils associated with a variable risk of developing sensorineural deafness, presenile cataract, and/or progressive nephropathy. The spectrum of mutations responsible for MYH9-RD is limited. We report five families, each with a novel MYH9 mutation. Two mutations, p.Val34Gly and p.Arg702Ser, affect the motor domain of myosin-9, whereas the other three, p.Met847_Glu853dup, p.Lys1048_Glu1054del, and p.Asp1447Tyr, hit the coiled-coil tail domain of the protein. The motor domain mutations were associated with more severe clinical phenotypes than those in the tail domain.
PMCID: PMC3546164  PMID: 23123319
MYH9-related disease; MYH9 gene; Mutational screening; Missense mutation; In frame deletion/duplication; Genotype–phenotype correlation
8.  A Japanese Family Suffering from Familial Juvenile Hyperuricemic Nephropathy due to a Rare Mutation of the Uromodulin Gene 
We report the case of a Japanese family suffering from familial juvenile hyperuricemic nephropathy (FJHN) due to a rare missense mutation of the uromodulin (UMOD) gene. An 18-year-old male presented with gout, hyperuricemia, and stage 3 chronic kidney disease. Mostly, FJHN is caused by a mutation altering the cystine residue of UMOD/Tamm-Horsfall protein. However, in the present case, a T688C mutation was identified in exon 4, resulting in amino acid substitution with arginine replacing tryptophan at position 230 (Trp230Arg). This mutation was also found in his brother and father with the same phenotype, indicating autosomal dominant inheritance. The affected amino acid was conserved in 200 healthy Japanese controls. Therefore, mutation T688C most likely causes rare structural and/or functional abnormalities in UMOD/Tamm-Horsfall protein.
PMCID: PMC3482064  PMID: 23197950
Chronic kidney disease; Familial juvenile hyperuricemic nephropathy; Gene; mutation; Uromodulin
9.  A Novel CRYGD Mutation (p.Trp43Arg) Causing Autosomal Dominant Congenital Cataract in a Chinese Family 
Human Mutation  2011;32(1):E1939-E1947.
To identify the genetic defect associated with autosomal dominant congenital nuclear cataract in a Chinese family, molecular genetic investigation via haplotype analysis and direct sequencing were performed Sequencing of the CRYGD gene revealed a c.127T>C transition, which resulted in a substitution of a highly conserved tryptophan with arginine at codon 43 (p.Trp43Arg). This mutation co-segregated with all affected individuals and was not observed in either unaffected family members or in 200 normal unrelated individuals. Biophysical studies indicated that the p.Trp43Arg mutation resulted in significant tertiary structural changes. The mutant protein was much less stable than the wild-type protein, and was more prone to aggregate when subjected to environmental stresses such as heat and UV irradiation. © 2010 Wiley-Liss, Inc.
PMCID: PMC3035819  PMID: 21031598
CRYGD; autosomal dominant congenital cataract; ADCC); structure
10.  The role of sarcomere gene mutations in patients with idiopathic dilated cardiomyopathy 
European Journal of Human Genetics  2009;17(10):1241-1249.
We investigated a Danish cohort of 31 unrelated patients with idiopathic dilated cardiomyopathy (IDC), to assess the role that mutations in sarcomere protein genes play in IDC. Patients were genetically screened by capillary electrophoresis single strand conformation polymorphism and subsequently by bidirectional DNA sequencing of conformers in the coding regions of MYH7, MYBPC3, TPM1, ACTC, MYL2, MYL3, TNNT2, CSRP3 and TNNI3. Eight probands carried disease-associated genetic variants (26%). In MYH7, three novel mutations were found; in MYBPC3, one novel variant and two known mutations were found; and in TNNT2, a known mutation was found. One proband was double heterozygous. We find evidence of phenotypic plasticity: three mutations described earlier as HCM causing were found in four cases of IDC, with no history of a hypertrophic phase. Furthermore, one pedigree presented with several cases of classic DCM as well as one case with left ventricular non-compaction. Disease-causing sarcomere gene mutations were found in about one-quarter of IDC patients, and seem to play an important role in the causation of the disease. The genetics is as complex as seen in HCM. Thus, our data suggest that a genetic work-up should include screening of the most prominent sarcomere genes even in the absence of a family history of the disease.
PMCID: PMC2986634  PMID: 19293840
cardiomyopathies; dilated; heart failure; sarcomere gene mutations; DNA mutational analysis
11.  A novel PAX6 mutation in a large Chinese family with aniridia and congenital cataract 
Molecular Vision  2010;16:1141-1145.
To identify the disease-causing gene in a four-generation Chinese family affected with autosomal dominant aniridia and cataract.
All patients underwent full ophthalmic examination. For mutation analysis, a partial coding region (exons 5–14) of paired box gene 6 (PAX6) was sequenced with DNA from the proband. Single-strand conformation polymorphism analysis for exon 5 of PAX6 was performed to demonstrate co-segregation of the PAX6 mutation with aniridia in all family members and the absence of the mutation in the normal controls.
The proband and other patients in the family were affected with aniridia accompanied with congenital cataract. A novel heterozygous PAX6 mutation in exon 5 (c.475_491del17, p.Arg38ProfsX12) was identified, which was predicted to generate a frameshift and create a premature termination codon. This mutation co-segregated with the affected individuals in the family and did not exist in unaffected family members and 100 unrelated normal controls.
A novel deletion mutation in the PAX6 gene was identified in a Chinese family with aniridia and congenital cataract. Our study expands the mutation spectrum of PAX6.
PMCID: PMC2901194  PMID: 20664694
12.  Hypertrophic cardiomyopathy: from mutation to functional analysis of defective protein 
Croatian Medical Journal  2011;52(3):384-391.
To analyze the genesis of hypertrophic cardiomyopathy on a large cohort of patients from molecular genetics point of view and perform the functional analysis of the 3D molecular model of defective myosin-7 protein in silico.
The study enrolled 153 patients with diagnosed hypertrophic cardiomyopathy from different parts of the Czech Republic. DNA samples were analyzed for mutations in exons 21 and 22 of the MYH7 gene, which have been associated with high mutation clustering. The 3D model of human myosin-7 was built using the x-ray structure of nucleotide-free scallop myosin S1 as the structural template. We performed de novo structure prediction of mutant and wild type peptides spanning the 769-788 amino acids region of the myosin-7 protein.
The Arg870His and Asp778Val amino acid alterations were found in 2 unrelated patients with a severe form of hypertrophic cardiomyopathy. The Asp778Val variation was chosen for subsequent 3D molecular modeling in silico. The mutation of the Asp by Val not only changes the character of the interaction pattern with other amino acids or ions but Val, being a small hydrophobic amino acid, can also completely change the stability of the region.
Mutation location in the MYH7 gene and changes in amino acid composition may have a crucial negative impact on the outcome of the disease in patients with hypertrophic cardiomyopathy. In addition, a mutation that changes the charge of the amino acid is more likely to affect protein function than a conservative mutation.
PMCID: PMC3118724  PMID: 21674835
13.  Germline MutY Human Homologue Mutations and Colorectal Cancer: A Multisite Case-Control Study 
Gastroenterology  2008;136(4):1251-1260.
Background & Aims
The MutY human homologue (MYH) gene is a member of the base-excision repair pathway involved in the repair of oxidative DNA damage. The objective of this study was to determine colorectal cancer (CRC) risk associated with mutations in the MYH gene.
A total of 3811 CRC cases and 2802 controls collected from a multisite CRC registry were screened for 9 germline MYH mutations; subjects with any mutation underwent screening of the entire MYH gene. Logistic regression was used to estimate age- and sex-adjusted odds ratios (AOR). Clinicopathologic and epidemiologic data were reviewed to describe the phenotype associated with MYH mutation status and assess for potential confounding and effect modification.
Twenty-seven cases and 1 control subject carried homozygous or compound heterozygous MYH mutations (AOR, 18.1; 95% confidence interval, 2.5–132.7). CRC cases with homozygous/compound heterozygous mutations were younger at diagnosis (P = .01), had a higher proportion of right-sided (P = .01), synchronous cancers (P < .01), and personal history of adenomatous polyps (P = .003). Heterozygous MYH mutations were identified in 87 CRC cases and 43 controls; carriers were at increased risk of CRC (AOR, 1.48; 95% confidence interval, 1.02–2.16). There was a higher prevalence of low-frequency microsatellite instability (MSI) in tumors from heterozygous and homozygous/compound heterozygous MYH mutation carriers (P = .02); MSI status modified the CRC risk associated with heterozygous MYH mutations (P interaction < .001).
Homozygous/compound heterozygous MYH mutations account for less than 1% of CRC cases. Heterozygous carriers are at increased risk of CRC. Further studies are needed to understand the possible interaction between the base excision repair and low-frequency MSI pathways.
PMCID: PMC2739726  PMID: 19245865
14.  The molecular defect in type IIB von Willebrand disease. Identification of four potential missense mutations within the putative GpIb binding domain. 
Journal of Clinical Investigation  1991;87(4):1227-1233.
Type IIB von Willebrand Disease (vWD) is characterized by the selective loss of large von Willebrand Factor (vWF) multimers from plasma, presumably due to their increased reactivity with platelets and subsequent clearance from the circulation. Using the PCR, one of a panel of four potential missense mutations was identified in each of the 14 patients studied from 11 unrelated families. None of these substitutions was encountered in a large panel of normal DNAs. These changes all represent C----T transitions at CpG dinucleotides, proposed "hot spots" for mutation in the human genome. The four resulting amino acid substitutions, Arg543----Trp, Arg545----Cys, Val553----Met, and Arg578----Gln, are all clustered within the GpIb binding domain of vWF. Disruption of this latter functional domain may explain the pathogenesis of Type IIB vWD. By sequence polymorphism analysis, the Arg543----Trp substitution was shown to have occurred as at least two independent mutational events. This latter observation, along with the identification of mutations in all 14 patients studied and their localization to the GpIb binding domain, all strongly suggest that these substitutions represent the authentic defects responsible for Type IIB vWD. This panel of mutations may provide a useful diagnostic tool for the majority of patients with Type IIB vWD.
PMCID: PMC295141  PMID: 1672694
15.  Prognostic implications of novel beta cardiac myosin heavy chain gene mutations that cause familial hypertrophic cardiomyopathy. 
Journal of Clinical Investigation  1994;93(1):280-285.
Three novel beta cardiac myosin heavy chain (MHC) gene missense mutations, Phe513Cys, Gly716Arg, and Arg719Trp, which cause familial hypertrophic cardiomyopathy (FHC) are described. One mutation in exon 15 (Phe513Cys) does not alter the charge of the encoded amino acid, and affected family members have a near normal life expectancy. The Gly716Arg mutation (exon 19; charge change of +1) causes FHC in three family members, one of whom underwent transplantation for heart failure. The Arg719Trp mutation (exon 19; charge change of -1) was found in four unrelated FHC families with a high incidence of premature death and an average life expectancy in affected individuals of 38 yr. A comparable high frequency of disease-related deaths in four families with the Arg719Trp mutation suggests that this specific gene defect directly accounts for the observed malignant phenotype. Further, the significantly different life expectancies associated with the Arg719Trp vs. Phe513Cys mutation (P < 0.001) support the hypothesis that mutations which alter the charge of the encoded amino acid affect survival more significantly than those that produce a conservative amino acid change.
PMCID: PMC293763  PMID: 8282798
16.  A novel mutation of the Keratin 12 gene responsible for a severe phenotype of Meesmann's corneal dystrophy 
Molecular Vision  2007;13:975-980.
To determine if a mutation within the coding region of the keratin 12 gene (KRT12) is responsible for a severe form of Meesmann's corneal dystrophy.
A family with clinically identified Meesmann's corneal dystrophy was recruited and studied. Electron microscopy was performed on scrapings of corneal epithelial cells from the proband. Mutations in the KRT12 gene were sought using direct genomic sequencing of leukocyte DNA from two affected and two unaffected family members. Subsequently, the observed mutation was screened in all available family members using polymerase chain reaction and direct sequencing.
A heterozygous missense mutation (Arg430Pro) was found in exon 6 of KRT12 in all 14 affected individuals studied. Unaffected family members and 100 normal controls were negative for this mutation.
We have identified a novel mutation in the KRT12 gene that is associated with a symptomatic phenotype of Meesmann's corneal dystrophy. This mutation results in a substitution of proline for arginine in the helix termination motif that may disrupt the normal helix, leading to a dramatic structural change of the keratin 12 protein.
PMCID: PMC2774455  PMID: 17653038
17.  Congenital Hypogonadotropic Hypogonadism Due to GNRH Receptor Mutations in Three Brothers Reveal Sites Affecting Conformation and Coupling 
PLoS ONE  2012;7(6):e38456.
Congenital hypogonadotropic hypogonadism (CHH) is characterized by low gonadotropins and failure to progress normally through puberty. Mutations in the gene encoding the GnRH receptor (GNRHR1) result in CHH when present as compound heterozygous or homozygous inactivating mutations. This study identifies and characterizes the properties of two novel GNRHR1 mutations in a family in which three brothers display normosmic CHH while their sister was unaffected. Molecular analysis in the proband and the affected brothers revealed two novel non-synonymous missense GNRHR1 mutations, present in a compound heterozygous state, whereas their unaffected parents possessed only one inactivating mutation, demonstrating the autosomal recessive transmission in this kindred and excluding X-linked inheritance equivocally suggested by the initial pedigree analysis. The first mutation at c.845 C>G introduces an Arg substitution for the conserved Pro 282 in transmembrane domain (TMD) 6. The Pro282Arg mutant is unable to bind radiolabeled GnRH analogue. As this conserved residue is important in receptor conformation, it is likely that the mutation perturbs the binding pocket and affects trafficking to the cell surface. The second mutation at c.968 A>G introduces a Cys substitution for Tyr 323 in the functionally crucial N/DPxxY motif in TMD 7. The Tyr323Cys mutant has an increased GnRH binding affinity but reduced receptor expression at the plasma membrane and impaired G protein-coupling. Inositol phosphate accumulation assays demonstrated absent and impaired Gαq/11 signal transduction by Pro282Arg and Tyr323Cys mutants, respectively. Pretreatment with the membrane permeant GnRHR antagonist NBI-42902, which rescues cell surface expression of many GNRHR1 mutants, significantly increased the levels of radioligand binding and intracellular signaling of the Tyr323Cys mutant but not Pro282Arg. Immunocytochemistry confirmed that both mutants are present on the cell membrane albeit at low levels. Together these molecular deficiencies of the two novel GNRHR1 mutations lead to the CHH phenotype when present as a compound heterozygote.
PMCID: PMC3367945  PMID: 22679506
18.  Missense mutation in PFKM associated with muscle-type phosphofructokinase deficiency in the Wachtelhund dog 
Molecular and cellular probes  2012;26(6):243-247.
Hereditary muscle-type phosphofructokinase (PFK) deficiency causing intermittent hemolytic anemia and exertional myopathy due to a single nonsense mutation in PFKM has been previously described in English Springer and American Cocker Spaniels, Whippets, and mixed breed dogs. We report here on a new missense mutation associated with PFK deficiency in Wachtelhunds.
Coding regions of the PFKM gene were amplified from genomic DNA and/or cDNA reverse-transcribed from RNA of EDTA blood of PFK-deficient and clinically healthy Wachtelhunds and control dogs. The amplicons were sequenced and compared to the published canine PFKM sequence. A point mutation (c.550C>T, in the coding sequence of PFKM expressed in blood) was found in all 4 affected Wachtelhunds. This missense mutation results in an amino acid substitution of arginine (Arg) to tryptophan (Trp) at position 184 of the protein expressed in blood (p.Arg184Trp). The mutation is located within an alpha-helix, and based on the SIFT analysis, this amino acid substitution is not tolerated. Amplifying the region around this mutation and digesting the PCR fragment with the restriction enzyme MspI, produces fragments that readily differentiate between PFK-deficient, carrier, and normal animals. Furthermore, we document 2 additional upstream PFKM exons expressed in canine testis but not in blood.
Despite their similar phenotypic appearance and use for hunting, Wachtelhunds and English Springer Spaniels are not thought to have common ancestors. Thus, it is not surprising that different mutations are responsible for PFK deficiency in these breeds. Knowledge of the molecular basis of PFK deficiency in Wachtelhunds provides an opportunity to screen and control the spread of this deleterious trait.
PMCID: PMC3485442  PMID: 22446493
Hemolytic anemia; Red cell defect; Myopathy; Hereditary disease; Dog
19.  Double mutation (R124H, N544S) of TGFBI in two sisters with combined expression of Avellino and lattice corneal dystrophies 
Molecular Vision  2009;15:974-979.
The R124H mutation of the keratoepithelin gene (TGFBI) causes Avellino corneal dystrophy whereas the N544S mutation of this same gene gives rise to lattice corneal dystrophy. We now report two cases with both R124H and N544S mutations of TGFBI.
Genomic DNA and cDNA were isolated from the proband and family members and were subjected to polymerase chain reaction–mediated amplification of exons 1–17 of TGFBI. The amplification products were directly sequenced. Allele-specific cloning and sequencing were applied to evaluate the compound heterozygous mutation.
Molecular genetic analysis revealed that the proband and one sister harbored both a heterozygous CGC→CAC (Arg→His) mutation at codon 124 and a heterozygous AAT→AGT (Asn→Ser) mutation at codon 544 of TGFBI. Slit-lamp examination revealed multiple granular regions of opacity and lattice lines in the corneal stroma of the proband and her sister with the double mutation. Allele-specific cloning and sequencing revealed that the R124H and N544S mutations are on different chromosomes.
As far as we are aware, this is the first report of a patient with a double mutation (R124H, N544S) of TGFBI causing an autosomal dominant form of corneal dystrophy. The clinical manifestations of the two cases with both R124H and N544S mutations appeared to be a summation of Avellino and lattice corneal dystrophies.
PMCID: PMC2684562  PMID: 19461933
20.  MYH9 Genetic Variants Associated With Glomerular Disease: What Is the Role for Genetic Testing? 
Seminars in nephrology  2010;30(4):409-417.
Genetic variation in MYH9, encoding nonmuscle myosin IIA heavy chain, has been associated recently with increased risk for kidney disease. Previously, MYH9 missense mutations have been shown to cause the autosomal-dominant MYH9 (ADM9) spectrum, characterized by large platelets, leukocyte Döhle bodies, and, variably, sensorineural deafness, cataracts, and glomerulopathy. Genetic testing is indicated for familial and sporadic cases that fit this spectrum. By contrast, the MYH9 kidney risk variant is characterized by multiple intronic single nucleotide polymorphisms, but the causative variant has not been identified. Disease associations include human immunodeficiency virus-associated collapsing glomerulopathy, focal segmental glomerulosclerosis, hypertension-attributed end-stage kidney disease, and diabetes-attributed end-stage kidney disease. One plausible hypothesis is that the MYH9 kidney risk variant confers a fragile podocyte phenotype. In the case of hypertension-attributed kidney disease, it remains unclear if the hypertension is a contributing cause or a consequence of glomerular injury. The MYH9 kidney risk variant is strikingly more common among individuals of African descent, but only some will develop clinical kidney disease in their lifetime. Thus, it is likely that additional genes and/or environmental factors interact with the MYH9 kidney risk variant to trigger glomerular injury. A preliminary genetic risk stratification scheme, using 10 single nucleotide polymorphisms, may estimate lifetime risk for kidney disease. Nevertheless, at present, no role has been established for genetic testing as part of personalized medicine, but testing should be considered in clinical studies of glomerular diseases among populations of African descent. Such studies will address critical questions pertaining to MYH9-associated kidney disease, including mechanism, course, and response to therapy.
PMCID: PMC3097395  PMID: 20807613
Focal segmental glomerulosclerosis; HIV-associated nephropathy; hypertensive nephrosclerosis; chronic kidney disease; end-stage kidney disease; African American
21.  Serial Observations and Mutational Analysis of an Adoptee with Family History of Hypertrophic Cardiomyopathy 
Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disease with an autosomal dominant mode of transmission. Comprehensive genetic screening of several genes frequently found mutated in HCM is recommended for first-degree relatives of HCM patients. Genetic testing provides the means to identify those at risk of developing HCM and to institute measures to prevent sudden cardiac death (SCD). Here, we present an adoptee whose natural mother and maternal relatives were known be afflicted with HCM and SCD. The proband was followed closely from age 6 to 17 years, revealing a natural history of the progression of clinical findings associated with HCM. Genetic testing of the proband and her natural mother, who is affected by HCM, revealed that they were heterozygous for both the R719Q and T1513S variants in the cardiac beta-myosin heavy chain (MYH7) gene. The proband's ominous family history indicates that the combination of the R719Q and T1513S variants in cis may be a “malignant” variant that imparts a poor prognosis in terms of the disease progression and SCD risk.
PMCID: PMC2838361  PMID: 20309391
22.  Molecular and biochemical characterization of a unique mutation in CCS, the human copper chaperone to superoxide dismutase 
Human Mutation  2012;33(8):1207-1215.
Copper is a trace metal that readily gains and donates electrons, a property that renders it desirable as an enzyme cofactor but dangerous as a source of free radicals. To regulate cellular copper metabolism, an elaborate system of chaperones and transporters has evolved, although no human copper chaperone mutations have been described to date. We describe a child from a consanguineous family who inherited a homozygous mutations in the SLC33A1, encoding an acetyl CoA transporter, and in CCS, encoding the copper chaperone for superoxide dismutase. The CCS mutation, p.Arg163Trp, predicts substitution of a highly conserved arginine residue at position 163 with tryptophan in domain II of CCS, which interacts directly with SOD1. Biochemical analyses of the patient’s fibroblasts, mammalian cell transfections, immunoprecipitation assays, and Lys7Δ (CCS homolog) yeast complementation support the pathogenicity of the mutation. Expression of CCS was reduced and binding of CCS to SOD1 impaired. As a result this mutation causes reduced SOD1 activity and may impair other mechanisms important for normal copper homeostasis. CCS-Arg163Trp represents the primary example of a human mutation in a gene coding for a copper chaperone.
PMCID: PMC3399931  PMID: 22508683
CCS; SOD1; copper; chaperone
23.  Novel ELANE Gene Mutation in a Korean Girl with Severe Congenital Neutropenia 
Journal of Korean Medical Science  2011;26(12):1646-1649.
Severe congenital neutropenia is a heterozygous group of bone marrow failure syndromes that cause lifelong infections. Mutation of the ELANE gene encoding human neutrophil elastase is the most common genetic alteration. A Korean female pediatric patient was admitted because of recurrent cervical lymphadenitis without abscess formation. She had a past history of omphalitis and isolated neutropenia at birth. The peripheral blood showed a markedly decreased absolute neutrophil count, and the bone marrow findings revealed maturation arrest of myeloid precursors at the promyelocyte to myelocyte stage. Her direct DNA sequencing analysis demonstrated an ELANE gene mutation (c.607G > C; p.Gly203Arg), but her parents were negative for it. She showed only transient response after subcutaneous 15 µg/kg/day of granulocyte colony stimulating factor administration for six consecutive days. During the follow-up observation period, she suffered from subsequent seven febrile illnesses including urinary tract infection, septicemia, and cellulitis.
PMCID: PMC3230029  PMID: 22148006
Severe Congenital Neutropenia; Neutrophil Elastase
24.  Coagulopathy in patients with hemorrhagic fever with renal syndrome. 
Hemorrhagic fever with renal syndrome in Korea (Korean hemorrhagic fever) is an acute viral disease characterized by fever, hemorrhage and renal failure. In Korean patients, the disease manifests more distinctive bleeding tendencies than those of hemorrhagic fever with renal syndrome found in western countries. To investigate the nature and role of the coagulation, fibrinolysis, kinin and immune system in the pathogenesis of such a hemorrhagic manifestation, alterations of these systems were assessed from the early phase of the disease. Decreased platelet count and shortened platelet survival were observed with giant platelets in the peripheral blood. The marked prolongations of bleeding time, prothrombin time and partial thromboplastin time were noticed with the decreased plasma activities of coagulation factors II, V, VIII, IX and X. Shortened half life of fibrinogen, increased fibrinogen-fibrin degradation product, with decreased plasma levels and activities of plasminogen, alpha 2-plasmin inhibitor and antithrombin III were found. On thrombelastogram, the existence of procoagulant activity was confirmed, and prolonged reaction time and clot formation time with decreased maximum amplitude were observed. The appearance of circulating immune complexes was found along with decreased C3 and normal C4 in the serum. Significant decrease of serum C3 was evident in the patients with disseminated intravascular coagulation. These findings of coagulopathy were normalized within ten days of the illness in most cases. Therefore, it can be concluded that disseminated intravascular coagulation and thrombocytopenia in the early phase, and azotemia developing later might play an important role in the pathogenesis of bleeding tendency in Korean hemorrhagic fever.
PMCID: PMC3053648  PMID: 3151765
25.  A mutation in FBN1 disrupts profibrillin processing and results in isolated skeletal features of the Marfan syndrome. 
Journal of Clinical Investigation  1995;95(5):2373-2378.
Dermal fibroblasts from a 13-yr-old boy with isolated skeletal features of the Marfan syndrome were used to study fibrillin synthesis and processing. Only one half of the secreted profibrillin was proteolytically processed to fibrillin outside the cell and deposited into the extracellular matrix. Electron microscopic examination of rotary shadowed microfibrils made by the proband's fibroblasts were indistinguishable from control cells. Sequencing of the FBN1 gene revealed a heterozygous C to T transition at nucleotide 8176 resulting in the substitution of a tryptophan for an arginine (R2726W), at a site immediately adjacent to a consensus sequence recognized by a cellular protease. Six other individuals in the proband's family had the FBN1 mutation that segregated with tall stature. None of the affected individuals have cardiac or ocular manifestations of the Marfan syndrome. This mutation identifies a putative site for profibrillin to fibrillin processing, and is associated with isolated skeletal features of the Marfan syndrome, indicating that the FBN1 gene is one of the genes that determines height in the general population. The cellular effect of the mutation may be equivalent to a "null" FBN1 allele and may define the phenotype associated with FBN1 "null" alleles.
PMCID: PMC295860  PMID: 7738200

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