RR Lyrae Variables in Two Fields in the Spheroid of M31

We present Hubble Space Telescope observations taken with the Advanced Camera for Surveys Wide Field Channel of two fields near M32—between 4 and 6 kpc from the center of M31. The data cover a time baseline sufficient for the identification and characterization of 681 RR Lyrae variables of which 555 are ab-type and 126 are c-type. The mean magnitude of these stars is = 25.29 ± 0.05, where the uncertainty combines both the random and systematic errors. The location of the stars in the Bailey diagram and the ratio of c-type RR Lyraes to all types are both closer to RR Lyraes in Oosterhoff type I globular clusters in the Milky Way as compared with Oosterhoff II clusters. The mean periods of the ab-type and c-type RR Lyraes are = 0.557 ± 0.003 and = 0.327 ± 0.003, respectively, where the uncertainties in each case represent the standard error of the mean. When the periods and amplitudes of the ab-type RR Lyraes in our sample are interpreted in terms of metallicity, we find the metallicity distribution function to be indistinguishable from a Gaussian with a peak at = –1.50 ± 0.02, where the quoted uncertainty is the standard error of the mean. Using a relation between RR Lyrae luminosity and metallicity along with a reddening of E(B – V) = 0.08 ± 0.03, we find a distance modulus of (m – M)_0 = 24.46 ± 0.11 for M31. We examine the radial metallicity gradient in the environs of M31 using published values for the bulge and halo of M31 as well as the abundances of its dwarf spheroidal companions and globular clusters. In this context, we conclude that the RR Lyraes in our two fields are more likely to be halo objects rather than associated with the bulge or disk of M31, in spite of the fact that they are located at 4-6 kpc in projected distance from the center

Developing a quick, cost-effective genetic screen for enamel disease

Amelogenesis imperfecta (AI) refers to a group of rare, inherited disorders characterised by abnormal enamel formation. According to the AI Leiden Open Variant Database (LOVD) hosted by Leeds University (http://dna2.leeds.ac.uk/LOVD/), there are 19 genes involved in non-syndromic AI that account for >90% of the known AI-causing mutations. Conventionally the identification of inherited gene mutations in a family would be done through family studies. However, with technological improvements and decreasing costs, next generation sequencing (NGS) technology has become the gold standard in the genetic research. Single molecule molecular inversion probe (smMIP) is an NGS based DNA sequencing approach that can selectively target and analyse thousands of genomic positions in a single reaction. It is superior in terms of cost, throughput, scalability, sensitivity, and specificity and can process hundreds of patients simultaneously. To identify mutations in AI patients, an smMIP method was adapted and validated that can be used as a first point of screening for all the future patients. The aim is to make diagnosis quicker for patients with known mutations and to provide extra resources to focus on the discovery of novel gene mutations

The Deepest Hubble Space Telescope Color-Magnitude Diagram of M32:Evidence for Intermediate-age Populations

We present the deepest optical color-magnitude diagram (CMD) to date of the local elliptical galaxy M32. We have obtained F435W and F555W photometries based on Hubble Space Telescope (HST) Advanced Camera for Surveys/High-Resolution Channel images for a region 110 '' from the center of M32 (F1) and a background field (F2) about 320 '' away from M32 center. Due to the high resolution of our Nyquist-sampled images, the small photometric errors, and the depth of our data (the CMD of M32 goes as deep as F435W similar to 28.5 at 50% completeness level), we obtain the most detailed resolved photometric study of M32 yet. Deconvolution of HST images proves to be superior than other standard methods to derive stellar photometry on extremely crowded HST images, as its photometric errors are similar to 2x smaller than other methods tried. The location of the strong red clump in the CMD suggests a mean age between 8 and 10 Gyr for [Fe/H] = -0.2 dex in M32. We detect for the first time a red giant branch bump and an asymptotic giant branch (AGB) bump in M32 which, together with the red clump, allow us to constrain the age and metallicity of the dominant population in this region of M32. These features indicate that the mean age of M32's population at similar to 2' from its center is between 5 and 10 Gyr. We see evidence of an intermediate-age population in M32 mainly due to the presence of AGB stars rising to M-F555W similar to -2.0. Our detection of a blue component of stars (blue plume) may indicate for the first time the presence of a young stellar population, with ages of the order of 0.5 Gyr, in our M32 field. However, it is likely that the brighter stars of this blue plume belong to the disk of M31 rather than to M32. The fainter stars populating the blue plume indicate the presence of stars not younger than 1 Gyr and/or BSSs in M32. The CMD of M32 displays a wide color distribution of red giant branch stars indicating an intrinsic spread in metallicity with a peak at [Fe/H] similar to -0.2. There is not a noticeable presence of blue horizontal branch stars, suggesting that an ancient population with [Fe/H] <-1.3 does not significantly contribute to the light or mass of M32 in our observed fields. M32's dominant population of 8-10 Gyr implies a formation redshift of 1 less than or similar to z(f) less than or similar to 2, precisely when observations of the specific star formation rates and models of "downsizing" imply galaxies of M32's mass ought to be forming their stars. Our CMD therefore provides a "ground truth" of downsizing scenarios at z = 0. Our background field data represent the deepest optical observations yet of the inner disk and bulge of M31. Its CMD exhibits a broad color spread of red giant stars indicative of its metallicity range with a peak at [Fe/H] similar to -0.4 dex, slightly more metal-poor than M32 in our fields. The observed blue plume consists of stars as young as 0.3 Gyr, in agreement with previous works on the disk of M31. The detection of bright AGB stars reveals the presence of intermediate-age population in M31, which is, however, less significant than that in M32 at our field's location

The Star Formation History of M32

We use deep HST ACS/HRC observations of a field within M32 (F1) and an M31 background field (F2) to determine the star formation history (SFH) of M32 from its resolved stellar population. We find that 2-5Gyr old stars contribute \som40%+/- 17% of M32's mass, while 55%+/-21% of M32's mass comes from stars older than 5 Gyr. The mass-weighted mean age and metallicity of M32 at F1 are =6.8+/-1.5 Gyr and =-0.01+/-0.08 dex. The SFH additionally indicates the presence of young (<2 Gyr old), metal-poor ([M/H]\sim-0.7) stars, suggesting that blue straggler stars contribute ~2% of the mass at F1; the remaining \sim3% of the mass is in young metal-rich stars. Line-strength indices computed from the SFH imply a light-weighted mean age and metallicity of 4.9 Gyr and [M/H] = -0.12 dex, and single-stellar-population-equivalent parameters of 2.9+/-0.2 Gyr and [M/H]=0.02+/-0.01 dex at F1 (~2.7 re). This contradicts spectroscopic studies that show a steep age gradient from M32's center to 1re. The inferred SFH of the M31 background field F2 reveals that the majority of its stars are old, with \sim95% of its mass already acquired 5-14 Gyr ago. It is composed of two dominant populations; \sim30%+/-7.5% of its mass is in a 5-8 Gyr old population, and \sim65%+/-9% of the mass is in a 8-14 Gyr old population. The mass-weighted mean age and metallicity of F2 are =9.2+/-1.2 Gyr and =-0.10+/-0.10 dex, respectively. Our results suggest that the inner disk and spheroid populations of M31 are indistinguishable from those of the outer disk and spheroid. Assuming the mean age of M31's disk at F2 (\sim1 disk scale length) to be 5-9 Gyr, our results agree with an inside-out disk formation scenario for M31's disk.Comment: Accepted to ApJ. 24 pages, 18 figures. A high-resolution version can be downloaded from http://www.astro.rug.nl/~monachesi/monachesi-sfh.pd

RR Lyrae variables in M32 and the disk of M31

We observed two fields near M32 with the Advanced Camera for Surveys/High Resolution Channel (ACS/HRC) on board the Hubble Space Telescope (HST). The main field, F1, is 1.8 arcmin from the center of M32; the second field, F2, constrains the M31 background, and is 5.4 arcmin distant. Each field was observed for 16-orbits in each of the F435W (narrow B) and F555W (narrow V) filters. The duration of the observations allowed RR Lyrae stars and other short-period variables to be detected. A population of RR Lyrae stars determined to belong to M32 would prove the existence of an ancient population in that galaxy, a subject of some debate. We detected 17 RR Lyrae variables in F1 and 14 in F2. A 1-sigma upper limit of 6 RR Lyrae variables belonging to M32 is inferred from these two fields alone. Use of our two ACS/WFC parallel fields provides better constraints on the M31 background, however, and implies that $7_{-3}^{+4}$ (68 % confidence interval) RR Lyrae variables in F1 belong to M32. We have therefore found evidence for an ancient population in M32. It seems to be nearly indistinguishable from the ancient population of M31. The RR Lyrae stars in the F1 and F2 fields have indistinguishable mean V-band magnitudes, mean periods, distributions in the Bailey diagram and ratios of RRc to RR(tot) types. However, the color distributions in the two fields are different, with a population of red RRab variables in F1 not seen in F2. We suggest that these might be identified with the detected M32 RR Lyrae population, but the small number of stars rules out a definitive claim.Comment: 19 pages, 18 figures, accepted Ap

Defects in the acid phosphatase ACPT cause recessive hypoplastic amelogenesis imperfecta

We identified two homozygous missense variants (c.428C>T, p.(T143M) and c.746C>T, p.(P249L)) in ACPT, the gene encoding Acid Phosphatase, Testicular, which segregate with hypoplastic Amelogenesis imperfecta (AI) in two unrelated families. ACPT is reported to play a role in odontoblast differentiation and mineralisation by supplying phosphate during dentine formation. Analysis by computerised tomography and scanning electron microscopy of a primary molar tooth from an individual homozygous for the c.746C>T variant, revealed an enamel layer that was hypoplastic but mineralised with prismatic architecture. These findings implicate variants in ACPT as a cause of early failure of amelogenesis during the secretory phase

Amelogenesis Imperfecta caused by N-Terminal Enamelin Point Mutations in Mice and Men is driven by Endoplasmic Reticulum Stress

‘Amelogenesis imperfecta’ (AI) describes a group of inherited diseases of dental enamel that have major clinical impact. Here, we identify the aetiology driving AI in mice carrying a p.S55I mutation in enamelin; one of the most commonly mutated proteins underlying AI in humans. Our data indicate that the mutation inhibits the ameloblast secretory pathway leading to ER stress and an activated unfolded protein response (UPR). Initially, with the support of the UPR acting in pro-survival mode, Enam(p.S55I) heterozygous mice secreted structurally normal enamel. However, enamel secreted thereafter was structurally abnormal; presumably due to the UPR modulating ameloblast behaviour and function in an attempt to relieve ER stress. Homozygous mutant mice failed to produce enamel. We also identified a novel heterozygous ENAM(p.L31R) mutation causing AI in humans. We hypothesize that ER stress is the aetiological factor in this case of human AI as it shared the characteristic phenotype described above for the Enam(p.S55I) mouse. We previously demonstrated that AI in mice carrying the Amelx(p.Y64H) mutation is a proteinopathy. The current data indicate that AI in Enam(p.S55I) mice is also a proteinopathy, and based on comparative phenotypic analysis, we suggest that human AI resulting from the ENAM(p.L31R) mutation is another proteinopathic disease. Identifying a common aetiology for AI resulting from mutations in two different genes opens the way for developing pharmaceutical interventions designed to relieve ER stress or modulate the UPR during enamel development to ameliorate the clinical phenotype

Mutations in the Beta Propeller WDR72 Cause Autosomal-Recessive Hypomaturation Amelogenesis Imperfecta

Healthy dental enamel is the hardest and most highly mineralized human tissue. Though acellular, nonvital, and without capacity for turnover or repair, it can nevertheless last a lifetime. Amelogenesis imperfecta (AI) is a collective term for failure of normal enamel development, covering diverse clinical phenotypes that typically show Mendelian inheritance patterns. One subset, known as hypomaturation AI, is characterised by near-normal volumes of organic enamel matrix but with weak, creamy-brown opaque enamel that fails prematurely after tooth eruption. Mutations in genes critical to enamel matrix formation have been documented, but current understanding of other key events in enamel biomineralization is limited. We investigated autosomal-recessive hypomaturation AI in a consanguineous Pakistani family. A whole-genome SNP autozygosity screen identified a locus on chromosome 15q21.3. Sequencing candidate genes revealed a point mutation in the poorly characterized WDR72 gene. Screening of WDR72 in a panel of nine additional hypomaturation AI families revealed the same mutation in a second, apparently unrelated, Pakistani family and two further nonsense mutations in Omani families. Immunohistochemistry confirmed intracellular localization in maturation-stage ameloblasts. WDR72 function is unknown, but as a putative β propeller is expected to be a scaffold for protein-protein interactions. The nearest homolog, WDR7, is involved in vesicle mobilization and Ca2+-dependent exocytosis at synapses. Vesicle trafficking is important in maturation-stage ameloblasts with respect to secretion into immature enamel and removal of cleaved enamel matrix proteins via endocytosis. This raises the intriguing possibility that WDR72 is critical to ameloblast vesicle turnover during enamel maturation

Mutations in CNNM4 Cause Jalili Syndrome, Consisting of Autosomal-Recessive Cone-Rod Dystrophy and Amelogenesis Imperfecta

The combination of recessively inherited cone-rod dystrophy (CRD) and amelogenesis imperfecta (AI) was first reported by Jalili and Smith in 1988 in a family subsequently linked to a locus on chromosome 2q11, and it has since been reported in a second small family. We have identified five further ethnically diverse families cosegregating CRD and AI. Phenotypic characterization of teeth and visual function in the published and new families reveals a consistent syndrome in all seven families, and all link or are consistent with linkage to 2q11, confirming the existence of a genetically homogenous condition that we now propose to call Jalili syndrome. Using a positional-candidate approach, we have identified mutations in the CNNM4 gene, encoding a putative metal transporter, accounting for the condition in all seven families. Nine mutations are described in all, three missense, three terminations, two large deletions, and a single base insertion. We confirmed expression of Cnnm4 in the neural retina and in ameloblasts in the developing tooth, suggesting a hitherto unknown connection between tooth biomineralization and retinal function. The identification of CNNM4 as the causative gene for Jalili syndrome, characterized by syndromic CRD with AI, has the potential to provide new insights into the roles of metal transport in visual function and biomineralization

Heimler Syndrome is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6

Heimler syndrome (HS) is a rare recessive disorder characterized by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities and occasional or late onset retinal pigmentation. We ascertained eight families with HS, and - using a whole exome sequencing approach - identified biallelic mutations in PEX1 or PEX6 in six of them. Loss of function mutations in both genes are known causes of a spectrum of autosomal recessive peroxisome biogenesis disorders (PBDs), including Zellweger syndrome. PBDs are characterized by leukodystrophy, hypotonia, SNHL, retinopathy, and skeletal, craniofacial, and liver abnormalities. We demonstrate that each HS family has at least one hypomorphic allele that results in extremely mild peroxisomal dysfunction. Although individuals with HS share some subtle clinical features found in PBDs, the overlap is minimal and the diagnosis was not suggested by routine blood and skin fibroblast analyses used to detect PBDs. In conclusion, our findings define Heimler syndrome as a mild PBD, expanding the pleiotropy of mutations in PEX1 and PEX6