Genetic Defects in TAPT1 Disrupt Ciliogenesis and Cause a Complex Lethal Osteochondrodysplasia.

The evolutionarily conserved transmembrane anterior posterior transformation 1 protein, encoded by TAPT1, is involved in murine axial skeletal patterning, but its cellular function remains unknown. Our study demonstrates that TAPT1 mutations underlie a complex congenital syndrome, showing clinical overlap between lethal skeletal dysplasias and ciliopathies. This syndrome is characterized by fetal lethality, severe hypomineralization of the entire skeleton and intra-uterine fractures, and multiple congenital developmental anomalies affecting the brain, lungs, and kidneys. We establish that wild-type TAPT1 localizes to the centrosome and/or ciliary basal body, whereas defective TAPT1 mislocalizes to the cytoplasm and disrupts Golgi morphology and trafficking and normal primary cilium formation. Knockdown of tapt1b in zebrafish induces severe craniofacial cartilage malformations and delayed ossification, which is shown to be associated with aberrant differentiation of cranial neural crest cells.

Prolonged Right Ventricular Ejection Delay in Brugada Syndrome Depends on the Type of SCN5A Variant　- Electromechanical Coupling Through Tissue Velocity Imaging as a Bridge Between Genotyping and Phenotyping.

BACKGROUND: Patients with Brugada syndrome (BrS) and a history of syncope or sustained ventricular arrhythmia have longer right ventricular ejection delays (RVEDs) than asymptomatic BrS patients. Different types ofSCN5Avariants leading to different reductions in sodium current (INa) may have different effects on conduction delay, and consequently on electromechanical coupling (i.e., RVED). Thus, we investigated the genotype-phenotype relationship by measuring RVED to establish whether BrS patients carrying more severeSCN5Avariants leading to premature protein truncation (T) and presumably 100%INareduction have a longer RVED than patients carrying missense variants (M) with different degrees ofINareduction.Methods and Results:There were 34 BrS patients (mean [±SD] age 43.3±12.9 years; 52.9% male) carrying anSCN5Avariant and 66 non-carriers in this cross-sectional study. Patients carrying aSCN5Avariant were divided into T-carriers (n=13) and M-carriers (n=21). Using tissue velocity imaging, RVED and left ventricular ejection delay (LVED) were measured as the time from QRS onset to the onset of the systolic ejection wave at the end of the isovolumetric contraction. T-carriers had longer RVEDs than M-carriers (139.3±15.1 vs. 124.8±11.9 ms, respectively; P=0.008) and non-carriers (127.7±17.3 ms, P=0.027). There were no differences in LVED among groups. CONCLUSIONS: Using the simple, non-invasive echocardiographic parameter RVED revealed a more pronounced 'electromechanical' delay in BrS patients carrying T variants ofSCN5A.

Kinetochore KMN network gene CASC5 mutated in primary microcephaly.

Several genes expressed at the centrosome or spindle pole have been reported to underlie autosomal recessive primary microcephaly (MCPH), a neurodevelopmental disorder consisting of an important brain size reduction present since birth, associated with mild-to-moderate mental handicap and no other neurological feature nor associated malformation. Here, we report a mutation of CASC5 (aka Blinkin, or KNL1, or hSPC105) in MCPH patients from three consanguineous families, in one of which we initially reported the MCPH4 locus. The combined logarithm of odds score of the three families was >6. All patients shared a very rare homozygous mutation of CASC5. The mutation induced skipping of exon 18 with subsequent frameshift and truncation of the predicted protein. CASC5 is part of the KMN network of the kinetochore and is required for proper microtubule attachment to the chromosome centromere and for spindle-assembly checkpoint (SAC) activation during mitosis. Like MCPH gene ASPM, CASC5 is upregulated in the ventricular zone (VZ) of the human fetal brain. CASC5 binds BUB1, BUBR1, ZWINT-1 and interestingly it binds to MIS12 through a protein domain which is truncated by the mutation. CASC5 localized at the equatorial plate like ZWINT-1 and BUBR1, while ASPM, CEP152 and PCTN localized at the spindle poles in our patients and in controls. Comparison of primate and rodent lineages indicates accelerated evolution of CASC5 in the human lineage. Our data provide strong evidence for CASC5 as a novel MCPH gene, and underscore the role of kinetochore integrity in proper volumetric development of the human brain.

Oculocutaneous albinism type IV: A boy of Moroccan descent with a novel mutation in SLC45A2.

Oculocutaneous albinism type IV (OCA4 [MIM606574]) caused by mutations of the SLC45A2 gene is an autosomal recessive disorder of pigmentation characterized by reduced biosynthesis of melanin pigment in the skin, hair, and eye. We had the opportunity to examine a Belgian boy of Moroccan descent with clinically severe OCA and screened the mutation in his SLC45A2 gene. Sequencing of exon 1, of which the PCR product showed aberrant patterns in the SSCP gel, revealed that the patient was a homozygote for p.H38R mutation. We demonstrated that the p.H38R-mutant protein was functionally incapable of melanin synthesis using melanocyte cultures (under white cells; uw) established from a mouse model of OCA4. This is the second report of the occurrence of OCA4 in a member of an African ethnic group.

N1303K and IVS8-5T, clinical presentation within a family with atypical cystic fibrosis.

The CFTR genotype N1303K/IVS8-5T can cause very mild cystic fibrosis (CF) and congenital bilateral absence of the vas deferens (CBAVD). We report one family consisting of five affected patients in two generations, presenting minor symptoms of CF at different ages, segregating the CFTR mutations N1303K and IVS8-T5-TG13 in trans. Common features were chronic sinopulmonary symptoms and borderline or slightly elevated sweat chloride values. One patient had CBAVD.

High incidence of the CFTR mutations 3272-26A-->G and L927P in Belgian cystic fibrosis patients, and identification of three new CFTR mutations (186-2A-->G, E588V, and 1671insTATCA).

We have analyzed 143 unrelated Belgian patients with a positive diagnosis of cystic fibrosis (CF) for mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. An initial screening for 29 CFTR mutations led to mutation identification in 89.9% of the tested chromosomes. Subsequently an extensive analysis of the CFTR gene was performed by denaturating gradient gel electrophoresis (DGGE) in those patients with at least one unknown mutation after preliminary screening. In addition to 10 previously reported mutations we identified 2 new mutations 186-2A-->G and E588V. A third new mutation 1671insTATCA was identified during routine screening for DeltaF508. Two mutations were detected with a higher frequency than expected: 3272-26A-->G, which is the second most common mutation after DeltaF508 in our CF population with a frequency of 3.8%, and L927P (2.4%). The clinical data is presented for the mutations 186-2A-->G, E588V, 3272-26A-->G and L927P. The mutation data are useful for the Belgian population to supplement the initial screening set of mutations.

New ZMPSTE24 (FACE1) mutations in patients affected with restrictive dermopathy or related progeroid syndromes and mutation update.

Restrictive dermopathy (RD) is a rare and extremely severe congenital genodermatosis, characterized by a tight rigid skin with erosions at flexure sites, multiple joint contractures, low bone density and pulmonary insufficiency generally leading to death in the perinatal period. RD is caused in most patients by compound heterozygous or homozygous ZMPSTE24 null mutations. This gene encodes a metalloprotease specifically involved in lamin A post-translational processing. Here, we report a total of 16 families for whom diagnosis and molecular defects were clearly established. Among them, we report seven new ZMPSTE24 mutations, identified in classical RD or Mandibulo-acral dysplasia (MAD) affected patients. We also report nine families with one or two affected children carrying the common, homozygous thymine insertion in exon 9 and demonstrate the lack of a founder effect. In addition, we describe several new ZMPSTE24 variants identified in unaffected controls or in patients affected with non-classical progeroid syndromes. In addition, this mutation update includes a comprehensive search of the literature on previously described ZMPSTE24 mutations and associated phenotypes. Our comprehensive analysis of the molecular pathology supported the general rule: complete loss-of-function of ZMPSTE24 leads to RD, whereas other less severe phenotypes are associated with at least one haploinsufficient allele.

The mutation spectrum in RECQL4 diseases.

Mutations in the RECQL4 gene can lead to three clinical phenotypes with overlapping features. All these syndromes, Rothmund-Thomson (RTS), RAPADILINO and Baller-Gerold (BGS), are characterized by growth retardation and radial defects, but RAPADILINO syndrome lacks the main dermal manifestation, poikiloderma that is a hallmark feature in both RTS and BGS. It has been previously shown that RTS patients with RECQL4 mutations are at increased risk of osteosarcoma, but the precise incidence of cancer in RAPADILINO and BGS has not been determined. Here, we report that RAPADILINO patients identified as carriers of the c.1390+2delT mutation (p.Ala420_Ala463del) are at increased risk to develop lymphoma or osteosarcoma (6 out of 15 patients). We also summarize all the published RECQL4 mutations and their associated cancer cases and provide an update of 14 novel RECQL4 mutations with accompanying clinical data.

Somatic and gonadal mosaicism in Hutchinson-Gilford progeria.

We have studied a patient with Hutchinson-Gilford progeria (HGP). Sequence analysis of the LMNA gene demonstrated the presence of a c.1824 C > T (p.G608G) mutation, activating a cryptic splice donor site and leading to the formation of a truncated Lamin A protein. All molecularly characterized autosomal dominant HGP cases described so far result from de novo LMNA mutations, mostly originating on the paternal allele and are often linked with advanced paternal age. However, in our patient, the mutation was transmitted by the mother who showed somatic and germline mosaicism without HGP manifestations.