Heterozygotes For Mutations Research Articles

Association between genetic variants in the adiponectin gene and premature myocardial infarction

To investigate the relationship between adiponectin gene polymorphisms and premature myocardial infarction (PMI). A total of 306 PMI patients of Beijing Anzhen Hospital were identified from March 2013 to January 2015 using the case-control method, 412 patients with normal coronary angiography results served as the control group. 17 single nucleotide polymorphisms (SNPs) in adiponectin gene were selected and genotyped using mass spectrometry. The Chi-squared test was used to compare allele and genotype frequencies between PMI and control groups. The plasma adiponectin concentrations were measured using enzyme-linked immunoassay, and the relationship was analyzed between adiponectin level and SNPs. There was no significant difference in allele frequencies and in genotype frequencies between PMI patients and controls (P>0.05). Multivariate logistic regression models were used to estimate the correlation in additive, dominant and recessive genetic models, respectively. Analysis showed that rs2241766T>G was significant associated with PMI risk in a addition model in Chinese Han population(OR=1.446, 95%CI 1.006-2.079, P=0.035), and rs12629945G>A was significant association with PMI risk in a dominant model in Chinese Han population(OR=1.609, 95%CI 1.006-2.573, P=0.041). Adiponectin levels in PMI group were significantly lower than in control group ((863.3±112.8)μg/L vs.(910.4±117.1)μg/L, P=0.042). Adiponectin levels were significantly lower in patients with the homozygous mutation genotype (GG) compared to patients with the heterozygote mutant and wild type genotypes (GT+ TT) in adiponectin gene rs2241766 T>G polymorphisms ((859.4±98.1)μg/L vs. (908.9±113.1)μg/L, P=0.032). The rs2241766T>G and rs12629945G>A polymorphisms in the adiponectin gene were associated with PMI in Chinese Han population. Rs2241766T>G polymorphisms is linked with lower plasma adiponectin levels, and increased risk of PMI.

Influence of a HTR2B Stop Codon on Glucagon Homeostasis and Glucose Excursion in Non-Diabetic Men.

Limited data are available about the role of the serotonin 2B (5-HT2B) receptor in the function of human islets. This study aimed to test whether the 5-HT2B receptor contributes to glucose, insulin, and glucagon homeostasis in humans, utilizing a hereditary loss-of-function gene mutation in the receptor, which causes a 50% reduction in the production of the receptor protein in heterozygotes. This clinical study enrolled participants recruited by newspaper advertisements and from mental status examinations. A cohort of participants from a young Finnish founder population composed of 68 non-diabetic males with a mean age of 30 was divided into groups for comparison based on being a 5-HT2B receptor loss-of-function gene mutation (HTR2B Q20*) heterozygote carrier (n=11) or not (n=57). Serum levels of glucose, insulin, and glucagon were measured in a 5 h oral glucose tolerance test using a 75 g glucose challenge. Insulin resistance, insulin sensitivity, and beta cell activity were calculated using the homeostasis model assessment (HOMA2) and whole body insulin sensitivity index (WBISI), as well as the ratio of glucagon to insulin was noted. The areas under the curves (AUCs) were also determined. Concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were measured in cerebrospinal fluid (CSF). Covariate adjusted mean score comparisons were applied. Lower glucagon secretion and decreased glucose excursion were observed among HTR2B Q20* carriers as compared with individuals who were homozygotes for the wild-type Q20 allele (controls). No differences in insulin secretion, beta cell activity, insulin resistance, or insulin sensitivity were observed. The glucagon to insulin ratio differed between the HTR2B Q20* carriers and controls. CSF levels of 5-HIAA were similar between groups. Our findings indicate that the 5-HT2B receptor may contribute to the regulation of human glucagon and glucose homeostasis and the interplay between glucagon and insulin secretion.

Identification of biological pathways regulated by PGRN and GRN peptide treatments using transcriptome analysis.

Mutations in progranulin (PGRN) have been linked to two neurodegenerative disorders, heterozygote mutations with frontotemporal lobar degeneration (FTLD) and homozygote mutations with neuronal ceroid lipofuscinosis (NCL). Human PGRN is 593aa secreted growth factor, made up of seven and a half repeats of a highly conserved granulin motif that is cleaved to produce the granulin peptides A-G and paragranulin. While it is thought that PGRN protects against neurodegeneration through its role in inflammation and tissue repair, the role of PGRN and granulins in the nervous system is currently unclear. To better understand this, we prepared recombinant PGRN, granulin A-F and paragranulin, and used these to treat differentiated neuronal SH-SY5Y cells. Using RNA sequencing and bioinformatics techniques we investigated the functional effects of PGRN and the individual granulins upon the transcriptome. For PGRN treatment we show that the main effect of short-duration treatments is the down-regulation of transcripts, supporting that signalling pathway induction appears to be dominant effect. Gene ontology analysis, however, also supports the regulation of biological processes such as the spliceosome and proteasome in response to PGRN treatment, as well as the lysosomal pathway constituents such as CHMP1A, further supporting the role of PGRN in lysosomal function. We also show that the response to granulin treatments involves the regulation of numerous non-coding RNA's, and the granulins cluster into groups of similar activity on the basis of expression profile with paragranulin and PGRN having similar expression profiles, while granulins B, D, E and G appear more similar.

Mutation screening for the causative gene in a four-generation Chinese pedigree with progressive cardiac conduction defect

To define the potential causative gene mutation in a Chinese pedigree with progressive cardiac conduction defect (PCCD). Sanger sequencing was performed to define potential causative gene mutation in a four-generation family with 68 members including seven PCCD patients (5 male) from 2010 to 2015.No causative gene was detected by screening known candidate genes related to PCCD including SCN5A, NKX2.5 and LMNA.High-throughput sequencing technology on exon-enriched DNA was then used to search the causative genes in 2 patients and one normal family member. Eight new non-synonymous single nucleotide variants including AQP7 gene (exon5: c.T343C: p.Y115H), CACNA1B gene (NM_001243812: exon19: c.A2986G: p.T996A), CATSPERB gene (exon27: c.C3254G: p.P1085R), CLCA2 gene (exon11: c.G1725T: p.W575C), CLCA3P gene (ncRNA_intronic), MYLK-AS1 gene (ncRNA_intronic), TTN gene (ncRNA_UTR3), LMNA gene (LMNA: NM_170708: exon5: c.C922T: p.Q308X) were identified by comparing and filtering the results with known public databases.Then, more detailed biological analysis on these 8 genes was conducted.Traditional Sanger sequencing validated the exome sequencing results, and found that the mutation c. 1725G﹥T in gene CLCA2 segregated with the phenotype of this PCCD pedigree.The mutation c. 1725G﹥T in gene CLCA2 was thus be considered as the causative PCCD gene in this pedigree from the perspective of genetics and genomics. The heterozygote mutation c. 1725G﹥T in gene CLCA2 might be causative gene in this PCCD pedigree.This finding adds new gene mutation variant responsible for PCCD.

Prevalence of Pompe disease in 3,076 patients with hyperCKemia and limb-girdle muscular weakness.

We prospectively screened a large European cohort of patients presenting with hyperCKemia and/or limb-girdle muscular weakness (LGMW) for acid α-glucosidase (GAA) deficiency by dried blood spot (DBS) investigation. DBS were collected from 3,076 consecutive adult patients from 7 German and British neuromuscular centers. All specimens were investigated for GAA deficiency by fluorometry. Samples with reduced enzyme activity were subsequently investigated for GAA gene mutations. Of 3,076 patients with DBS samples, 232 patients (7.6%) showed low GAA enzyme activity. Of these 232 patients, 55 (24%) presented with isolated hyperCKemia and 176 (76%) with hyperCKemia and LGMW. With both features present, 94% of the patients showed a low enzymatic activity. Mutational analysis found GAA gene mutations in 74 patients (2.4%); herein 70 patients were heterozygote for the common GAA gene splice-site mutation c.-32-13T>G. The most common clinical presentation in the confirmed Pompe cohort was a limb-girdle phenotype (85.3%) combined with ventilatory insufficiency (61%). Isolated hyperCKemia was found in 12%, while 2.7 had hyperCKemia and ventilatory insufficiency only. In a large cohort of unselected adult patients with hyperCKemia and/or LGMW, we found a prevalence of late-onset Pompe disease of 2.4%. Therefore, targeted screening of such a population should be encouraged in clinical practice.

ADA2 deficiency: case report of a new phenotype and novel mutation in two sisters

The objective of this paper is todescribe the phenotype compound heterozygote for mutations in CECR1 in two children. We describe the clinical and immunological phenotype, including the assessment of ADA2...

Novel allelic mutations in murine Serca2 induce differential development of squamous cell tumors

Dominant mutations in the Serca2 gene, which encodes sarco(endo)plasmic reticulum calcium-ATPase, predispose mice to gastrointestinal epithelial carcinoma [1–4] and humans to Darier disease (DD) [14–17]. In this study, we generated mice harboring N-ethyl-N-nitrosourea (ENU)-induced allelic mutations in Serca2: three missense mutations and one nonsense mutation. Mice harboring these Serca2 mutations developed tumors that were categorized as either early onset squamous cell tumors (SCT), with development similar to null-type knockout mice [2,4] (aggressive form; M682, M814), or late onset tumors (mild form; M1049, M1162). Molecular analysis showed no aberration in Serca2 mRNA or protein expression levels in normal esophageal cells of any of the four mutant heterozygotes. There was no loss of heterozygosity at the Serca2 locus in the squamous cell carcinomas in any of the four lines. The effect of each mutation on Ca2+-ATPase activity was predicted using atomic-structure models and accumulated mutated protein studies, suggesting that putative complete loss of Serca2 enzymatic activity may lead to early tumor onset, whereas mutations in which Serca2 retains residual enzymatic activity result in late onset. We propose that impaired Serca2 gene product activity has a long-term effect on squamous cell carcinogenesis from onset to the final carcinoma stage through an as-yet unrecognized but common regulatory pathway.

Are anti-Müllerian hormone and its receptor polymorphism associated with the hormonal condition of undescended testes?

PurposeNumerous genetic and endocrine factors are involved in the process of testicular descent, but only a few genetic causes have been reported in human. The aim of this study was to investigate the density and distribution of single nucleotide polymorphisms (SNPs) anti-Müllerian hormone (AMH) and AMHRII receptors in cryptorchid patients and determine potential hormone imbalance connected with undescended testes by assessing the levels of AMH, Insulin-like factor 3 (INSL3) and inhibin B. Materials and methodsThe serum hormone levels (AMH, INSL3 and inhibin B) were compared in the two groups – cryptorchidism (n=105) and control group (n=58). The frequency of AMHRII −482 A>G, AMHRII IVS 10+77 A>G, AMHRII IVS 5–6 C>T, and AMH Ile49Ser polymorphisms among cryptorchid boys were compared with the control group. ResultsNone of the hormones levels were different between the cryptorchid and the control groups. All cases of IVS 5–6 C>T homozygote and heterozygote mutation were accompanied by an IVS 10+77 A>G and 482 A>G homozygote and heterozygote mutation. Interestingly, in most cases of all four polymorphisms, homozygote recessive genotype was associated with cases of cryptorchidism. However, the groups of patients were too small to draw definite conclusions. ConclusionThe AMHRII −482 A>G, AMHRII IVS 10+77 A>G, AMHRII IVS 5–6 C>T and AMH Ile49Ser genotypes should be determined in a much larger group of boys with cryptorchidism.

Essential light chain S195 phosphorylation is required for cardiac adaptation under physical stress.

Regulatory proteins of the sarcomere are pivotal for normal heart function and when affected by mutations are frequently causing cardiomyopathy. The exact function of these regulatory proteins and how mutations in these translate into distinct cardiomyopathy phenotypes remains poorly understood. Mutations in the essential myosin light chain (ELC) are linked to human cardiomyopathy characterized by a marked variability in disease phenotypes and high incidences of sudden death. Here we studied the role of the highly conserved S195 phosphorylation site of ELC using heterozygous adult zebrafish lazy susan (laz(m647)) in regulating contractile function in normal physiology and disease. Echocardiography revealed signs of systolic dysfunction in otherwise phenotypically unremarkable heterozygote mutants. However, after physical stress, heart function of laz heterozygous zebrafish severely deteriorated causing heart failure and sudden death. Mechanistically, we show that upon physical stress, ELCs become phosphorylated and lack of S195 dominant-negatively impairs ELC phosphorylation. In vitro motility analysis with native myosin from adult heterozygous hearts demonstrates that S195 loss, specifically following physical stress, results in altered acto-myosin sliding velocities and myosin binding cooperativity, causing reduced force generation and organ dysfunction. Using adult heterozygous zebrafish, we show that ELC S195 phosphorylation is pivotal for adaptation of cardiac function to augmented physical stress and we provide novel mechanistic insights into the pathogenesis of ELC-linked cardiomyopathy.

Compound heterozygote mutations in SPG7 in a family with adult-onset primary lateral sclerosis.

Objective:To identify the genetic defect for adult-onset primary lateral sclerosis (PLS) in a family with 5 patients.Methods:Whole-exome sequencing was performed to identify the shared genetic variants in 3 affected members in a PLS family with 5 affected individuals. Sanger sequencing was used for validation of the variants and for cosegregation analysis. Mitochondrial activity for both patients and unaffected siblings was measured using a SeaHorse metabolic analyzer.Results:Whole-exome sequencing and subsequent cosegregation analysis demonstrated that compound heterozygous missense variants L695P and I743T in SPG7 were the only mutations cosegregating with the disease in an autosomal recessive fashion in this family. The parents and siblings are genetically heterozygous and clinically unaffected. Functional studies suggested that the PLS-associated SPG7 mutants affect mitochondrial function when glucose is reduced.Conclusions:Compound heterozygote mutations in SPG7 are associated with adult-onset PLS, extending the spectrum of SPG7-linked neurologic diseases. Patients with the PLS phenotype should have genetic testing for paraplegin, especially when the condition is familial.

Extended longevity and survivorship during amino-acid starvation in a Drosophila Sir2 mutant heterozygote.

The regulation of energy homeostasis is pivotal to survive periods of inadequate nutrition. A combination of intricate pathways and proteins are responsible for maximizing longevity during such conditions. The sirtuin deacetylase Sir2 is well conserved from single-celled yeast to mammals, and it controls a number of downstream targets that are active during periods of extreme stress. Overexpression of Sir2 has been established to enhance survival of a number of model organisms undergoing calorie restriction, during which insulin receptor signalling (IRS) is reduced, a condition that itself can enhance survivorship during starvation. Increased Sir2 expression and reduced IRS result in an increase in the activity of the transcription factor foxo, an advantageous activation during stress but lethal when overly active. We have found that a lowered gene dosage of Sir2, in mutant heterozygotes, can extend normal longevity and greatly augment survivorship during amino-acid starvation in Drosophila. Additionally, these mutants, in either heterozygous or homozygous form, do not appear to have any disadvantageous effects upon development or cell growth of the organism unlike IRS mutants. These results may advance the understanding of the biological response to starvation and allow for the development of a model organism to mimic the ability of individuals to tolerate nutrient deprivation.

The Actin F352S Nemaline Myopathy Mutation Disrupts Indirect Flight Muscle Structure and Function in Drosophila

Nemaline myopathy is a congenital human muscle disorder characterized by masticatory, limb and respiratory weakness. Dominant negative disease-causing mutations have been identified in ten genes that notably encode sarcomeric thin filament proteins including α actin (ACTA1). While most of these mutations cause a loss of muscle function, the F352S actin mutation elevates myosin cross-bridge strain and steady-state isometric force production and, thereby, apparently increases contractile function in humans. To investigate the F352S-induced myopathic cascade from the level of single molecules through the level of whole muscle we generated transgenic Drosophila that express the mutation in Act88F, the indirect flight muscle (IFM) actin gene. Mutant heterozygotes were flightless. Fluorescent and electron microscopy revealed breaks in mutant IFM fibers and extensive myofibrillar disarray. For example, the highly ordered double hexagonal thin/thick filament lattice, at the periphery of myofibrils, was distorted with myofilaments occasionally losing longitudinal orientation. Z-lines showed streaming and formed “zebra bodies”. The microscopic alterations are consistent with inappropriate acto-myosin interaction, unevenly distributed force, and destructive hypercontraction. Interestingly, in vitro sliding velocities of purified IFM F-actin from wild-type (3.17±0.12 μm/s) vs. F352S mutant heterozygous (2.88±0.09 μm/s, mean±SEM) flies did not significantly differ. Similarly, no differences in maximum calcium-activated velocity (3.88±0.11 vs. 3.77±0.10 μm/s) or in cooperativity (nH = 2.13±0.27 vs. 2.62±0.46) were observed for F-actin in the presence of tropomyosin and troponin. However, F352S heterozygous filaments showed a significant (p < 0.01) increase in calcium sensitivity relative to control (pCa50 = 6.11 +/- 0.03 vs. 5.99 +/- 0.03), consistent with mutation-induced gain in molecular function. Going forward, our novel Drosophila model will be used to screen for in vivo modifiers of mutant muscle performance.Supported by NIH 2PO1 AR052354 (P.D. Allen PI; CFA Core D).

Two Symptomatic Patients with Atypical Heterozygous Artemis Mutation Along with Other Mutations Including TACI, While Parents with an Isolated Heterozygote Mutation Were Asymptomatic

Two Symptomatic Patients with Atypical Heterozygous Artemis Mutation Along with Other Mutations Including TACI, While Parents with an Isolated Heterozygote Mutation Were Asymptomatic

Progesterone Receptor Gene Polymorphism Promoter Region +331G/A Increases Risk of Endometriosis

Objective: To identify relationship between progesterone receptor&#x0D; gene polymorphism promoter region +331G/A with the risk of&#x0D; endometriosis.&#x0D; Method: An observational case-control study. Population are women&#x0D; with endometriosis and/or adenomyosis who have been performed&#x0D; laparotomy/laparoscopy at Obstetrics and Gynecology&#x0D; Department Dr. Mohammad Hoesin General Hospital Palembang,&#x0D; January-November 2013. Subjects fulfilled inclusion criteria, given&#x0D; informed consent and performed blood sampling continued by PCRRFLP.&#x0D; Results were divided into A/A genotype (homozygote mutant),&#x0D; G/A (heterozygote mutant), and G/G (homozygote wild type).&#x0D; Data were analyzed by SPSS 21.0 version.&#x0D; Result: PCR-RFLP results for+331G/A genotype were 26 (54.1%) in&#x0D; case group and 14 (26.4%) in control. +331A/A genotype was not&#x0D; found in both groups. There was significant increase risk of endometriosis&#x0D; in women carrying genotype +331G/A to those with genotype&#x0D; +331G/G with OR 3.29 (p

CYP2C19 polymorphisms in acute coronary syndrome patients undergoing clopidogrel therapy in Zhengzhou population.

The goal of this study was to explore the polymorphisms of CYP2C19 (CYP2C19*2, CYP2C19*3) in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) on clopidogrel therapy in Zhengzhou city for guidance on clinical medication and reduction in the incidence of thromboembolic events. Two hundred and thirty-four ACS patients undergoing PCI were included in the study, including 171 males (average age = 64.13 ± 12 years) and 63 females (average age = 67.86 ± 10.20 years). Pyrosequencing analysis detected CYP2C19*2/*3 genotypes, which were divided into wild-type homozygous C/C, mutant heterozygous C/T, and mutant homozygous T/T. This study further explored the relationship between CYP2C19 polymorphisms and clopidogrel resistance in ACS patients. Gene frequencies of C/C, C/T, and T/T for CYP2C19*2 were 39.74, 50, and 10.26%, respectively, while the frequencies of C/C, C/T, and T/T for CYP2C19*3 were 94.02, 5.55, and 0.43%, respectively. According to platelet aggregation analysis, 203 cases normally responded to clopidogrel (86.8%) and 31 cases were clopidogrel resistant (13.2%). There was a correlation between gender and genotype distribution but none between age and genotype. In addition, patients with clopidogrel resistance were treated with ticagrelor antiplatelet therapy instead of clopidogrel, and only 1 case in all patients suffered thrombotic events during a 3-12 month follow-up. In conclusion, CYP2C19*2/*3 polymorphisms may be associated with clopidogrel resistance. Wild-type homozygote and single mutant heterozygote of CYP2C19*2/*3 can be given a normal dose of clopidogrel, while carriers with single mutant homozygote or double mutant heterozygote require ticagrelor antiplatelet therapy as an alternative.

Association of N-acetyltransferase-2 polymorphism with an increased risk of coronary heart disease in a Chinese population.

We investigated the possible correlations between N-acetyltransferase-2 (NAT2) gene polymorphisms and the risk of coronary heart disease (CHD). CHD patients (113) and healthy controls (118) were enrolled from the First People's Hospital of Yuhang between January 2013 and June 2014. The patients were divided into mild CHD (N = 72) and severe CHD (N = 41) subgroups. DNA samples were extracted and the distributions of NAT2 polymorphisms were examined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Clinical characteristic indexes of severe CHD patients were also examined for relevant statistical analysis. WT, M1, M2, and M3 alleles were observed in both case and control groups. PCR-RFLP identified a wild-type homozygote, WT/WT; a mutant heterozygote, WT/Mx; and a mutant homozygote, Mx/Mx (x = 1, 2, and 3) variant of the NAT2 genotype. Mx/Mx differed significantly between case and control groups (P < 0.05); the frequencies of all four alleles did not differ significantly between case and control groups (P > 0.05). Slow acetylator genotype frequencies were notably higher in the case group than in the control group (P < 0.05). Individuals with the slow acetylator genotype were at 1.97-times higher risk of CHD and also displayed higher triglyceride and lower high-density lipoprotein cholesterol levels than those with the rapid acetylator genotype (P < 0.05). Therefore, the NAT2 polymorphism was believed to be associated with increased risk of CHD, with the NAT2 slow acetylator genotype serving as a risk factor for severe CHD in a Chinese population.

Genetic Screens for Determination of Mechanism of Action.

The search for new antifungal drugs and cell targets continues. During the discovery process, mechanism-of-action (MOA) studies are critical to the continued progress of the compound through the pipeline. There are many approaches that can be utilized in understanding the MOA. One of these approaches is a genetic screen utilizing the availability of Saccharomyces cerevisiae mutant libraries. Both null and heterozygous library mutants covering the entire genome of this model yeast are available. The desired phenotype when screening the new compound is either resistance (null mutants) or haploinsufficiency or loss of fitness (heterozygote mutants). Both types of mutants can be clustered by software into common targets that provide clues as to a pathway or other cell process. Below, methods are described for genetic screens.

Clinical study of the correlation between complement factor H polymorphism and age-related macular degeneration.

This study aimed to investigate the correlation between age-related macular degeneration (AMD) of the liver-kidney yin-deficiency type and complement factor H (CFH) polymorphism, and to determine whether the C allele of the T1277C (Y402H) variant is a risk factor for this condition. We performed a case-control investigation of 60 patients with liver-kidney yin-deficiency AMD and 60 normal control subjects. Peripheral blood was collected from each participant for DNA extraction. Following amplification by polymerase chain reaction, the DNA samples were sequenced, and polymorphism of the CFH gene was examined. Data were analyzed with the chi-square test, with P < 0.05 signifying statistical significance. The frequency of the C allele was significantly higher in the wet than in the dry AMD group (P = 0.044). In addition, the TC and CC genotypes were markedly more common in the former than in the control group (P = 0.013), and there was a significant difference in the distribution of the T and C alleles between wet AMD patients and control subjects (P < 0.05). Based on this, we conclude that liver-kidney yin-deficiency AMD is associated with the C allele and TC and CC genotypes of the CFH Y402H polymorphism. Among patients with this condition, CFH genotypes were normally distributed. The principal CFH genotypes that induce liver-kidney yin-deficiency AMD are the mutant homozygote CC and heterozygote TC forms. Moreover, C allele carriers are at higher risk of developing this disease.

Oral Symptoms and Bone Observations in Odonto-Hypophosphatasia

Hypophosphatasia (HPP) is an inherited skeletal disease caused by mutation of the gene encoding tissue non-specific alkaline phosphatase (TNSALP). Odonto-HPP is well known as the mildest of HPP. The manifestations involve only the teeth, such as premature primary teeth exfoliation caused by reduction of alveolar bone, enlarged dental pulp chamber, and dental defects. We report a case of a 9-years-old boy who developed HPP. He was observed from the primary dentition to the mixed dentition period. At initial presentation at our hospital, he had multiple premature exfoliation of primary teeth and reduction of the alveolar bone. HPP was suspected due to the low level of ALP activity in serum, his oral manifestation, and dental history. He was referred to a physician for the final diagnosis. Therefore his compound heterozygote mutations, c.1559 delT (T/delT) and c.407G > A (G/A), were found in TNSALP and he diagnosed with odonto-HPP. Even though these mutations were reported as being involved in odonto-HPP, his mineral densities tended to be lower than that of his age. It is therefore necessary to investigate the bone mineralization level in odonto-HPP without other bone symptoms. Moreover, ongoing enzyme-replacement therapy in odonto-HPP might improve dental abnormality and bone disorders.

Cobalamin C Deficiency Shows a Rapidly Progressing Maculopathy With Severe Photoreceptor and Ganglion Cell Loss

To describe in detail the retinal structure and function of a group of patients with cobalamin C (cblC) disease. Patients (n = 11, age 4 months to 15 years) with cblC disease (9/11, early onset) diagnosed by newborn screening underwent complete ophthalmic examinations, fundus photography, near-infrared reflectance imaging, and spectral-domain optical coherence tomography (SD-OCT). Electroretinograms (ERGs) were performed in a subset of patients. Patients carried homozygous or compound heterozygote mutations in the methylmalonic aciduria and homocystinuria type C (MMACHC) gene. Late-onset patients had a normal exam. All early-onset patients showed a maculopathy; older subjects had a retina-wide degeneration (n = 4; >7 years of age). In general, retinal changes were first observed before 1 year of age and progressed within months to a well-established maculopathy. Pseudocolobomas were documented in three patients. Measurable visual acuities ranged from 20/200 to 20/540. Nystagmus was present in 8/11 patients; 5/6 patients had normal ERGs; 1/6 had reduced rod-mediated responses. Spectral-domain OCT showed macular thinning, with severe ganglion cell layer (GCL) and outer nuclear layer (ONL) loss. Inner retinal thickening was observed in areas of total GCL/ONL loss. A normal lamination pattern in the peripapillary nasal retina was often seen despite severe central and/or retina-wide disease. Patients with early-onset cblC and MMACHC mutations showed an early-onset, unusually fast-progressing maculopathy with severe central ONL and GCL loss. An abnormally thickened inner retina supports a remodeling response to both photoreceptor and ganglion cell degeneration and/or an interference with normal development in early-onset cblC.