Maria Rosaria Piemontese

Sedlin Controls the ER Export of Procollagen by Regulating the Sar1 Cycle

A Tight Squeeze During intracellular transport, the export of procollagen from the endoplasmic reticulum is intriguing because procollagen is too large to fit into conventional coat protein complex II (COPII)–coated transport vesicles. Recent work has implicated the receptor TANGO1 in procollagen export. Now, Venditti et al. (p. 1668) report that TANGO1 recruits Sedlin—also known as TRAPPC2, a homolog of the yeast TRAPP subunit Trs20—and helps to allow COPII-coated carriers to grow large enough to incorporate procollagen. Sedlin, the product of the gene mutated in spondyloepiphyseal dyplasia tarda, acts to expand cargo containers to fit bulky procollagen. Newly synthesized proteins exit the endoplasmic reticulum (ER) via coat protein complex II (COPII) vesicles. Procollagen (PC), however, forms prefibrils that are too large to fit into typical COPII vesicles; PC thus needs large transport carriers, which we term megacarriers. TANGO1 assists PC packing, but its role in promoting the growth of megacarriers is not known. We found that TANGO1 recruited Sedlin, a TRAPP component that is defective in spondyloepiphyseal dysplasia tarda (SEDT), and that Sedlin was required for the ER export of PC. Sedlin bound and promoted efficient cycling of Sar1, a guanosine triphosphatase that can constrict membranes, and thus allowed nascent carriers to grow and incorporate PC prefibrils. This joint action of TANGO1 and Sedlin sustained the ER export of PC, and its derangement may explain the defective chondrogenesis underlying SEDT.

HOXA1 gene variants influence head growth rates in humans

We previously described a significant association between the HOXA1 G218 allele and increased head circumference in autism [Conciatori et al. (2004); Biol Psychiatry 55:413–419]. The present study reveals identical effects also in normal children. HOXA1 A218G alleles and sex explain as much as 10.9 and 6.8% of the variance in head circumference in 142 pediatric controls and in 191 autistic children, aged 3–16 years (F = 6.777, 3 and 141 df, P < 0.001 and F = 5.588, 3 and 190 df, P < 0.01, respectively). Instead, no association is found in 183 adult controls and in 35 pediatric fragile‐X patients. Therefore HOXA1 A218G alleles significantly influence head growth rates, but not final head size, in normal human development. This influence does not differ between normal and autistic children, whereas the lack of FMRP seemingly overwhelms HOXA1 effects in fragile‐X patients.

A new locus on 3p23-p25 for an autosomal-dominant limb-girdle muscular dystrophy, LGMD1H.

Limb-girdle muscular dystrophies (LGMDs) are a genetically heterogeneous group of neuromuscular disorders with a selective or predominant involvement of shoulder and pelvic girdles. We clinically examined 19 members in a four-generation Italian family with autosomal-dominant LGMD. A total of 11 subjects were affected. Clinical findings showed variable expressivity in terms of age at onset and disease severity. Five subjects presented with a slowly progressive proximal muscle weakness, in both upper and lower limbs, with onset during the fourth–fifth decade of life, which fulfilled the consensus diagnostic criteria for LGMD. Earlier onset of the disease was observed in a group of patients presenting with muscle weakness and/or calf hypertrophy, and/or occasionally high CK and lactate serum levels. Two muscle biopsies showed morphological findings compatible with MD associated with subsarcolemmal accumulation of mitochondria and the presence of multiple mitochondrial DNA deletions. A genome-wide scan performed using microsatellite markers mapped the disease on chromosome 3p23–p25.1 locus in a 25-cM region between markers D3S1263 and D3S3685. The highest two-point LOD score was 3.26 (θ=0) at marker D3S1286 and D3S3613, whereas non-parametric analysis reached a P-value=0.0004. Four candidate genes within the refined region were analysed but did not reveal any mutations. Our findings further expand the clinical and genetic heterogeneity of LGMDs.

An emerging phenotype of interstitial 15q25.2 microdeletions: clinical report and review.

Interstitial deletions of chromosome 15q25.2 are rare. To date, only nine patients with microdeletions within this chromosomal region have been described. Here, we report on a girl with severe speech and psychomotor delay, behavioral problems and mild dysmorphic features with a 1.6 Mb deletion in 15q25.2 region. In order to study the parental origin of the rearrangement, we analyzed selected SNPs in the deleted area in the patient and her parents, showing Mendelian incompatibilities suggesting a de novo deletion on the chromosome of maternal origin. By comparing the clinical and molecular features of our patient with five previously reported cases of an overlapping deletion, we suggest that 15q25.2 deletion is an emerging syndrome characterized by a distinct although variable spectrum of clinical manifestations, including mild dysmorphic features, neurodevelopmental delay, and a recognizable pattern of congenital malformation. Furthermore, our patient is the second one in which a behavioral phenotype characterized by hyperactivity, anxiety, and autistic features was reported, indicating that these features might be part of this new syndromic condition. Breakpoints of the deletion in the patient reported here are useful to better define the smallest region of overlap (SRO) among all the patients. Selected genes that are present in the hemizygous state and which might be important for the phenotype of these patients, are discussed in context of the clinical features. In conclusion, our patient increases the knowledge about the molecular and phenotypic consequences of interstitial 15q25.2 deletions, highlighting that deletions of this region may be responsible for a new microdeletion syndrome.

Multiple tumor types including leiomyoma and Wilms tumor in a patient with Gorlin syndrome due to 9q22.3 microdeletion encompassing the PTCH1 and FANC‐C loci

Gorlin syndrome or nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant condition mainly characterized by the development of mandibular keratocysts which often have their onset during the second decade of life and/or multiple basal cell carcinoma (BCC) normally arising during the third decade. Cardiac and ovarian fibromas can be found. Patients with NBCCS develop the childhood brain malignancy medulloblastoma (now often called primitive neuro‐ectodermal tumor [PNET]) in 5% of cases. The risk of other malignant neoplasms is not clearly increased, although lymphoma and meningioma can occur in this condition. Wilms tumor has been mentioned in the literature four times. We describe a patient with a 10.9 Mb 9q22.3 deletion spanning 9q22.2 through 9q31.1 that includes the entire codifying sequence of the gene PTCH1, with Wilms tumor, multiple neoplasms (lung, liver, mesenteric, gastric and renal leiomyomas, lung typical carcinoid tumor, adenomatoid tumor of the pleura) and a severe clinical presentation. We propose including leiomyomas among minor criteria of the NBCCS.

Linkage analysis of Fanconi anaemia in Italy and mapping of the complementation group A gene.

Abstract Fanconi anaemia (FA) is an autosomal recessive disease characterised by genetic heterogeneity, with at least five complementation groups (FA-A to FA-E). The FAC gene has been cloned and localised to 9q22.3. The most frequent defective gene, FAA, was recently mapped to chromosome 16q24.3, in a region of 10 cM between D16S498 and the telomere. Eleven FA-A and 16 unclassified Italian families were analysed by microsatellite markers. To define the localisation of the FAA locus further, microsatellites were analysed at 16q24. All the families were consistent with linkage, the highest lod score being observed with D16S1320. Evidence for common haplotypes was obtained in two genetic isolates from the Brenta basin and the Naples region. Autozygosity mapping and haplotype analysis suggest that the FAA locus is distal to D16S305.

Naevoid Basal Cell Carcinoma Syndrome in a 22-month-old Child Presenting with Multiple Basal Cell Carcinomas and a Fetal Rhabdomyoma

© 2015 The Authors. doi: 10.2340/00015555-1892 Journal Compilation

Characterization of endocrine features and genotype-phenotypes correlations in blepharophimosis-ptosis-epicanthus inversus syndrome type 1

AbstractObjectiveBlepharophimosis syndrome (BPES) is an autosomal dominant genetic condition resulting from heterozygous mutations in the FOXL2 gene and clinically characterized by an eyelid malformation associated (type I) or not (type II) with premature ovarian failure. The distinction between the two forms is critical for female patients, as it may allow to predict fertility and to plan an appropriate therapy. Identifying an underlying causative mutation is not always predictive of the clinical type of BPES since genotype–phenotype correlations are not yet fully delineated. Here, we describe the clinical and hormonal phenotypes of three female patients with BPES type 1 from two novel families, correlate their phenotypes with identified mutations, and investigate the effects of hormone replacement therapy (HRT). MethodsClinical, biochemical, and genetic evaluation were undertaken in all the patients and genotype–phenotype correlation was analyzed. The effects of substitutive hormonal therapy on secondary sexual characteristics development and induction of menarche were evaluated. ResultsAll patients presented with primary amenorrhea or other signs of ovarian dysfunction. Two distinct mutations, a missense p.H104R change and an in-frame p.A222_A231dup10 duplication in the FOXL2 gene were identified. Observed phenotypes were not in accordance with the prediction based on the current genotype–phenotype correlations. HRT significantly improved secondary sexual characteristics development, as well as the induction of menarche.ConclusionsThis study highlights the importance of early recognition of BPES and emphasizes the need of personalized therapy and follow-up in female patients carrying distinct FOXL2 mutations.

Ehlers-Danlos syndrome versus cleidocranial dysplasia

Dear Sir, The early identification of hereditary syndromes is essential for planning medical and surgical interventions for reducing the risk of complications [1]. Unfortunately, clinical phenotypes of hereditary syndromes in the first years of life and in mild cases are often poorly characterized. Some disease symptoms are also common to several different genetic conditions. Cleidocranial dysplasia (CCD, OMIM #119600) is a genetic condition that predominantly affects the skeletal system. Typical CCD features include persistently open skull sutures, clavicular hypoplasia/aplasia, and dental anomalies [2,3]. CCD is caused by a heterozygous loss-of-function mutation in the RUNX2 gene [2,3]. However, the abnormal shoulder and arm mobility commonly observed in CCD is also typical of other syndromes, particularly hypermobile Ehlers-Danlos syndrome (EDS-HT). EDS-HT is marked by joint laxity with minimal skin changes and no skin fragility [4] but does not have additional specific clinical features and cannot be diagnosed through laboratory tests. The child characterized in this report was initially misdiagnosed with EDS-HT when the correct diagnosis was CCD. CCD was confirmed by genetic findings but not until several years later. The male proband was the second child born to healthy, non-consanguineous Caucasian parents. The family history was unremarkable and did not indicate a history of mental retardation, genetic diseases, or birth defects. The child was born at 35 weeks of gestational age as the result of a premature membrane rupture after an uneventful pregnancy. At birth, he weighed 2,700 gr and had a body length of 45.5 cm, occipital frontal diameter of 30 cm, and an APGAR score of 9/10. The patient’s medical history after reaching school age was unremarkable, and he had normal body and psychomotor growth. However, delayed anterior fontanel closure and prolonged deciduous dentition retention were reported. At nine years of age, the patient experienced constant bilateral shoulder dislocation associated with bilateral flat foot and the delayed eruption of permanent teeth. The patient was evaluated by a pediatrician with experience in the clinical genetics field and was diagnosed with EDS-HT. At 13 years of age, the patient entered the pediatric

Linkage analysis in two large Italian pedigrees affected with nail patella syndrome

Nail patella syndrome (NPS) or osteo-onychodysplasia, is an autosomal dominant disorder characterised by nail dysplasia, absent or hypoplastic patellae, iliac horns and nephropathy. Previous studies have demonstrated linkage of the nail patella locus to the ABO and adenylate kinase loci on human chromosome 9q34. Recently, informative recombination events placed the NPS locus within a 1–2 cM interval within D9S60 and the AK1 gene. We describe here linkage analysis performed in two large Italian pedigrees with 10 and 11 members affected, respectively. A set of highly informative markers have been analysed and the allele segregation in the two families confirmed the linkage to chromosome 9. The presence of three recombination events allows definition of the critical region with a centrometric boundary between markers D9S1881 and D9S1840 and a telomeric boundary between markers D9S315 and D9S290.