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Jeanne Amiel

Publications and source records attributed to Jeanne Amiel.

At least 19 recordsLinked to original sources
PubMed2024

The characterization of new de novo CACNA1G variants affecting the intracellular gate of Cav3.1 channel broadens the spectrum of neurodevelopmental phenotypes in SCA42ND.

PURPOSE: Missense de novo variants in CACNA1G, which encodes the Cav3.1 T-type calcium channel, have been associated with a severe, early-onset form of cerebellar disorder with neurodevelopmental deficits (SCA42ND). We explored a large series of pediatric cases carrying heterozygous variants in CACNA1G to further characterize genotype-phenotype correlations in SCA42ND. METHODS: We describe 19 patients with congenital CACNA1G-variants, including 6 new heterozygotes of the recurrent SCA42ND variants, p.(Ala961Thr) and p.(Met1531Val), and 8 unreported variants, including 7 missense variants, mainly de novo. We carried out genetic and structural analyses of all variants. Patch-clamp recordings were performed to measure their channel activity. RESULTS: We provide a consolidated clinical description for the patients carrying p.(Ala961Thr) and p.(Met1531Val). The new variants associated with the more severe phenotypes are found in the Cav3.1 channel intracellular gate. Calcium currents of these Cav3.1 variants showed slow inactivation and deactivation kinetics and an increase in window current, supporting a gain of channel activity. On the contrary, the p.(Met197Arg) variant (IS4-S5 loop) resulted in a loss of channel activity. CONCLUSION: This detailed description of several de novo missense pathogenic variants in CACNA1G, including 13 previously reported cases, supports a clinical spectrum of congenital CACNA1G syndrome beyond spinocerebellar ataxia.

Humans↗
PubMed2006

Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome.

A clinically recognizable 9q subtelomeric deletion syndrome has recently been established. Common features seen in these patients are severe mental retardation, hypotonia, brachycephaly, flat face with hypertelorism, synophrys, anteverted nares, cupid bow or tented upper lip, everted lower lip, prognathism, macroglossia, conotruncal heart defects, and behavioral problems. The minimal critical region responsible for this 9q subtelomeric deletion (9q-) syndrome has been estimated to be <1 Mb and comprises the euchromatin histone methyl transferase 1 gene (EHMT1). Previous studies suggested that haploinsufficiency for EHMT1 is causative for 9q subtelomeric deletion syndrome. We have performed a comprehensive mutation analysis of the EHMT1 gene in 23 patients with clinical presentations reminiscent of 9q subtelomeric deletion syndrome. This analysis revealed three additional microdeletions that comprise the EHMT1 gene, including one interstitial deletion that reduces the critical region for this syndrome. Most importantly, we identified two de novo mutations--a nonsense mutation and a frameshift mutation--in the EHMT1 gene in patients with a typical 9q- phenotype. These results establish that haploinsufficiency of EHMT1 is causative for 9q subtelomeric deletion syndrome.

Abnormalities, Multiple↗
PubMed2005

Molecular consequences of PHOX2B missense, frameshift and alanine expansion mutations leading to autonomic dysfunction.

Heterozygous mutations of the PHOX2B gene account for a broad variety of disorders of the autonomic nervous system, either isolated or combined, including congenital central hypoventilation syndrome (CCHS), tumours of the sympathetic nervous system and Hirschsprung disease. In CCHS, the prevalent mutation is an expansion of a 20-alanine stretch ranging from +5 to +13 alanines, whereas frameshift and missense mutations are found occasionally. To determine the molecular basis of impaired PHOX2B function, we assayed the transactivation and DNA binding properties of wild-type and mutant PHOX2B proteins. Furthermore, we investigated aggregate formation by proteins with polyalanine tract expansions ranging from +5 to +13 alanines using immunofluorescence of transfected cells and gel filtration of in vitro translated proteins. We found that transactivation of the dopamine beta-hydroxylase promoter by PHOX2B proteins with frameshift and missense mutations was abolished or severely curtailed, as was in vitro DNA binding although the proteins localized to the nucleus. The transactivation potential of proteins with polyalanine tract expansions declined with increasing length of the polyalanine stretch, and DNA binding was affected for an expansion of +9 alanines and above. Cytoplasmic aggregation in transfected cells was only observed for the longest expansions, whereas even the short expansion mutants were prone to form multimers in vitro. Such a tendency to protein misfolding could explain loss of transactivation for alanine expansion mutations. However, additional mechanisms such as toxic gain-of-function may play a role in the pathogenic process.

Animals↗
PubMed2005

Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma.

Hereditary predisposition to neuroblastoma accounts for less than 5% of neuroblastomas and is probably heterogeneous. Recently, a predisposition gene has been mapped to 16p12-p13, but has not yet been identified. Occurrence of neuroblastoma in association with congenital central hypoventilation and Hirschsprung's disease suggests that genes, involved in the development of neural-crest-derived cells, may be altered in these conditions. The recent identification of PHOX2B as the major disease-causing gene in congenital central hypoventilation prompted us to test it as a candidate gene in familial neuroblastoma. We report a family with three first-degree relatives with neuroblastic tumours (namely two ganglioneuromas and one neuroblastoma) in one branch and two siblings with Hirschsprung's disease in another branch. A constitutional R100L PHOX2B mutation was identified in all three patients affected with tumours. We also report a germline PHOX2B mutation in one patient treated for Hirschsprung's disease who subsequently developed a multifocal neuroblastoma in infancy. Both mutations disrupt the homeodomain of the PHOX2B protein. No loss of heterozygosity at the PHOX2B locus was observed in the tumour, suggesting that haplo-insufficiency, gain of function or dominant negative effects may account for the oncogenic effects of these mutations. These observations identify PHOX2B as the first predisposing gene to hereditary neuroblastic tumours.

Adult↗
PubMed2005

Adams-Oliver syndrome and hepatoportal sclerosis: occasional association or common mechanism?

Adams-Oliver syndrome (AOS) is characterized by the association of scalp and skull defects and abnormalities of terminal limbs. Congenital heart malformations have also been reported. Hepatoportal sclerosis (HPS) is a rare cause of portal hypertension in children characterized by abnormalities of intra-hepatic portal veins, portal fibrosis, and nodular regeneration. Etiopathogenesis of these rare disorders remains unclear, but the hypothesis of vascular thrombotic mechanism has been suggested. Association of both syndromes has been reported in only one child. We now report on two unrelated children with AOS and HPS, one child harboring a factor V Leiden mutation. We hypothesize that the association of both disorders may not be fortuitous and reinforces the idea that AOS and HPS may share a vascular thrombotic mechanism.

Abnormalities, Multiple↗
PubMed2005

PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome.

The Phox2b gene is necessary for autonomic nervous-system development. Phox2b-/- mice die in utero with absent autonomic nervous system circuits, since autonomic nervous system neurons either fail to form or degenerate. We first identified the Phox2b human ortholog, PHOX2B, as the gene underlying congenital central hypoventilation syndrome (CCHS, or Ondine curse), with an autosomal dominant mode of inheritance and de novo mutation at the first generation. We have subsequently shown that heterozygous mutations of PHOX2B may account for several combined or isolated disorders of autonomic nervous-system development--namely, tumors of the sympathetic nervous system (TSNS), such as neuroblastoma and late-onset central hypoventilation syndrome. Here, we report the clinical and molecular assessments of a cohort of 188 probands with CCHS, either isolated or associated with Hirschsprung disease and/or TSNS. The mutation-detection rate was 92.6% (174/188) in our series, and the most prevalent mutation was an in-frame duplication leading to an expansion of +5 to +13 alanines in the 20-alanine stretch at the carboxy terminal of the protein. Such findings suggest PHOX2B mutation screening as a simple and reliable tool for the diagnosis of CCHS, independent of the clinically variable phenotype. In addition, somatic mosaicism was detected in 4.5% of parents. Most interestingly, analysis of genotype-phenotype interactions strongly supports the contention that patients with CCHS who develop malignant TSNS will harbor either a missense or a frameshift heterozygous mutation of the PHOX2B gene. These data further highlight the link between congenital malformations and tumor predisposition when a master gene in development is mutated.

Animals↗
PubMed2005

Failure to detect an 8p22-8p23.1 duplication in patients with Kabuki (Niikawa-Kuroki) syndrome.

Kabuki syndrome (KS) is a rare MCA/MR syndrome with an estimated frequency of 1/32 000 in Japan. This syndrome is characterized by postnatal growth retardation, distinctive facial features, dermatoglyphic anomalies, skeletal dysplasia, and mental retardation. The molecular basis of KS remains unknown. Recently, Milunsky and Huang reported on six unrelated patients with a clinical diagnosis of KS and an 8p22-8p23.1 duplication using comparative genomic hybridization and BAC-FISH studies. Also, they suggested that a paracentric inversion may contribute to the occurrence of KS. In the present study, 24 patients with a clinical diagnosis of KS based on Niikawa-Kuroki criteria have been collected. They were tested for the presence of an 8p duplication using the same clones as described by Milunsky and Huang. Our results do not confirm the previously described association between KS and an 8p22-8p23.1 duplication.

Abnormalities, Multiple↗
PubMed2005

The French Congenital Central Hypoventilation Syndrome Registry: general data, phenotype, and genotype.

OBJECTIVE: To analyze the main clinical features, genetic mutations, and outcomes of patients of the French Congenital Central Hypoventilation Syndrome (CCHS) Registry. DESIGN: A country-wide cohort established throughout a long-term multicenter effort. PATIENTS: Seventy French patients with CCHS (29 male patients and 41 female patients). METHODS: The following items were analyzed: the most important moments of the disease course; the main clinical characteristics; associated pathologic conditions; management; clinical outcome; and genetic mutations. RESULTS: An average of four new cases of CCHS per year was observed in the last 5 years. Thus, the incidence may be estimated to be 1 per 200,000 live births in France. The median age at diagnosis was 3.5 months (range, 0.5 to 15 months) before 1995 and < 2 weeks in the last 5 years (p = 0.01). CCHS occurred in isolation in 58 of 70 patients. In the remainder, it was associated with Hirschsprung disease (HSCR) [nine patients], Hirschsprung and neural crest tumor (two patients), and growth hormone deficiency (one patient). Among the 50 patients who lived beyond 1 year of age, all but one received nighttime ventilation, with 10 of them (20%) receiving it noninvasively. Three patients (6%) required daytime ventilatory support in addition to nighttime ventilation. The overall mortality rate was 38% (95% confidence interval [CI], 27 to 49%). The median age at death was 3 months (range, 0.4 months to 21 years). The 2-year mortality rate was greater in male patients than in female patients (p = 0.02; relative risk [RR], 2.71; 95% CI, 1.14 to 6.47) but was not affected by HSCR (p = 0.93; RR, 0.95; 95% CI, 0.28 to 3.2). The 43 patients who are currently alive (11 men; sex ratio, 0.4) have a mean age of 9 years (range, 2 months to 27 years). Among the 34 patients tested thus far, heterozygous mutations of the paired-like homeobox gene 2B (PHOX2B) gene were found in 31 patients (91%). CONCLUSION: Our four major findings are the extreme rarity of CCHS, the improved recognition over time, the lack of effect of HSCR on the mortality rate, and the high frequency of PHOX2B mutations.

Female↗
PubMed2005

Autonomic function in children with congenital central hypoventilation syndrome and their families.

STUDY OBJECTIVES: Congenital central hypoventilation syndrome (CCHS) is a genetic disorder characterized by failure of automatic control of breathing in the absence of obvious anatomic lesions. There have been several reports suggesting that CCHS patients display autonomic dysregulation. Pulse arterial tonometry (PAT) is a novel technique that provides noninvasive moment-to-moment measurements of sympathetic tone changes to the cutaneous vascular bed. We hypothesized that autonomic function as measured by PAT would be altered in children with CCHS. DESIGN: Prospective study. SETTING: CCHS Family Conference, Orlando, FL, and the local community in Louisville, KY. PARTICIPANTS: Nineteen CCHS patients and 31 parents as well as 24 control children and 15 adult control subjects. INTERVENTIONS: Children with CCHS and their parents underwent sympathetic challenges (vital capacity sigh and cold hand pressor test) and a test of reactive hyperemia (brachial artery occlusion) while PAT was continuously monitored from the right hand. Control children and control adults underwent the same procedure. MEASUREMENTS AND RESULTS: The maximal change of the PAT signal compared to the preceding baseline was averaged and expressed as percentage change for each of the challenges. The magnitude of sympathetic discharge-induced attenuation of PAT signal following a sigh was reduced in CCHS children compared to control subjects for both the vital capacity sighs and the cold hand pressor test. There were no differences observed in the magnitude of PAT attenuation between parents of children with CCHS and control adults. No differences were observed between either CCHS and control subjects or CCHS parents and adult control subjects for the brachial artery occlusion test. CONCLUSION: CCHS patients show an attenuated response to endogenous sympathetic stimulation, supporting the presence of autonomic nervous system dysfunction as a consistent feature of this condition. No differences were found in parents of children with CCHS compared to control adults, consistent with the finding that CCHS is primarily the result of a de novo gene mutation.

Autonomic Nervous System↗
PubMed2004

Polyalanine expansions in human.

Beside the well-known polyglutamine expansions involved in several neurodegenerative disorders, convergent recent findings pointed to the expansion of polyalanine stretches as a disease mechanism in congenital malformations, skeletal dysplasia and nervous system anomalies. Polyalanine stretches have been predicted in roughly 500 human proteins among which nine have been ascribed to disease phenotype by expansion of polyalanines. The function of polyalanine stretches is largely unknown. This paper aims to review the rapidly growing evidences for a disease-causing mechanism common to expansion of homopolymeric tracts whatever the amino acid involved is.

Animals↗
PubMed2004

Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma.

Neuroblastoma (NB) is a frequent pediatric tumor for which recurrent somatic rearrangements are known. Germline mutations of predisposing gene(s) are suspected on the basis of rare familial cases and the association of NB with other genetically determined congenital malformations of neural crest-derived cells--namely, Hirschsprung disease (HSCR) and/or congenital central hypoventilation syndrome (CCHS). We recently identified the paired-like homeobox 2B (PHOX2B) gene as the major disease-causing gene in isolated and syndromic CCHS, which prompted us to regard it as a candidate gene in NB. Here, we report on germline mutations of PHOX2B in both a familial case of NB and a patient with the HSCR-NB association. PHOX2B, therefore, stands as the first gene for which germline mutations predispose to NB.

Base Sequence↗
PubMed2004

Genetics and early disturbances of breathing control.

Early disturbances in breathing control, including apneas of prematurity and apparently life-threatening events, account for some cases of sudden infant death syndrome and for a rare disorder called congenital central hypoventilation syndrome (CCHS). Data suggesting a genetic basis for CCHS have been obtained. Recently, we found heterozygous de novo mutations of the PHOX2B gene in 18 of 29 individuals with CCHS. Most mutations consisted of five to nine alanine expansions within a 20-residue polyalanine tract, probably resulting from nonhomologous recombination. Other mutations, generally inherited from one of the parents, in the coding regions of genes involved in the endothelin and RET signaling pathways and in the brain-derived-neurotrophic factor (BDNF) gene have been found in a few CCHS patients. Interestingly, all these genes are involved in the development of neural crest cells. Targeted disruption of these genes in mice has provided information on the pathophysiological mechanisms underlying CCHS. Despite the identification of these genes involved in breathing control, none of the genetically engineered mice developed to date replicate the full human CCHS respiratory phenotype. Recent insights into the genetic basis for CCHS may shed light on the genetics of other early disturbances in breathing control, such as apnea of prematurity and sudden infant death syndrome.

Animals↗
PubMed2004

Molecular screening of the ZFHX1B gene in prenatally diagnosed isolated agenesis of the corpus callosum.

OBJECTIVE: Agenesis of the corpus callosum (ACC) is the most common malformation of the central nervous system and may be associated with mental retardation. ACC is found in 40% of the cases of Mowat-Wilson syndrome (MWS), a polytopic embryonic defect including a distinctive facial gestalt, severe mental retardation, epilepsy and postnatal microcephaly as constant features. Other manifestations involve Hirschsprung disease, cardiac defects, renal abnormalities and hypospadias. Among this broad spectrum of malformations recently associated with haploinsufficiency of the zinc finger homeobox 1B gene (ZFHX1B), ACC can therefore be the only feature to be detected prenatally. Thus, we studied a group of 18 fetuses terminated for ACC and performed mutational analysis of the ZFHX1B gene in six selected cases. METHODS: Diagnosis of agenesis of the ACC was performed by prenatal echography survey. Screening for ZFHX1B deletions was performed by poly (CA) microsatellite markers studies and real-time semi-quantitative PCR. Mutational analysis was performed by single-strand conformation polymorphisms analysis (SSCP). RESULTS: Neither deletion encompassing the ZFHX1B locus nor mutation could be detected in any of the six fetuses analysed. CONCLUSION: ZFHX1B is not a major gene in isolated ACC. However, analysis of MWS should be considered in the differential diagnosis of ACC, especially when the facial features raise the possibility of MWS.

Agenesis of Corpus Callosum↗
PubMed2004

PHOX2B gene mutation in a patient with late-onset central hypoventilation.

Congenital central hypoventilation syndrome, which is related to abnormal autonomic control of breathing and typically manifests at birth, was recently associated with PHOX2B gene mutations. In contrast, central hypoventilation with later onset constitutes a poorly defined group of unknown etiology. Here, we report on the identification of a de novo heterozygous PHOX2B mutation in a patient with central hypoventilation manifesting in childhood. This finding suggests that some of these cases may be genetically determined and allelic to congenital central hypoventilation syndrome.

Base Sequence↗
PubMed2003

Noradrenergic neuronal development is impaired by mutation of the proneural HASH-1 gene in congenital central hypoventilation syndrome (Ondine's curse).

Congenital central hypoventilation syndrome (CCHS, Ondine's curse) is a rare disorder of the chemical control of breathing. It is frequently associated with a broad spectrum of dysautonomic symptoms, suggesting the involvement of genes widely expressed in the autonomic nervous system. In particular, the HASH-1-PHOX2A-PHOX2B developmental cascade was proposed as a candidate pathway because it controls the development of neurons with a definitive or transient noradrenergic phenotype, upstream from the RET receptor tyrosine kinase and tyrosine hydroxylase. We recently showed that PHOX2B is the major CCHS locus, whose mutation accounts for 60% of cases. We also studied the proneural HASH-1 gene and identified a heterozygous nucleotide substitution in three CCHS patients. To analyze the functional consequences of HASH-1 mutations, we developed an in vitro model of noradrenergic differentiation in neuronal progenitors derived from the mouse vagal neural crest, reproducing in vitro the HASH-PHOX-RET pathway. All HASH-1 mutant alleles impaired noradrenergic neuronal development, when overexpressed from adenoviral constructs. Thus, HASH-1 mutations may contribute to the CCHS phenotype in rare cases, consistent with the view that the abnormal chemical control of breathing observed in CCHS patients is due to the impairment of noradrenergic neurons during early steps of brainstem development.

Alleles↗
PubMed2003

A genomic rearrangement resulting in a tandem duplication is associated with split hand-split foot malformation 3 (SHFM3) at 10q24.

Split hand-split foot malformation (SHFM) is characterized by hypoplasia/aplasia of the central digits with fusion of the remaining digits. SHFM is usually an autosomal dominant condition and at least five loci have been identified in humans. Mutation analysis of the DACTYLIN gene, suspected to be responsible for SHFM3 in chromosome 10q24, was conducted in seven SHFM patients. We screened the coding region of DACTYLIN by single-strand conformation polymorphism and sequencing, and found no point mutations. However, Southern, pulsed field gel electrophoresis and dosage analyses demonstrated a complex rearrangement associated with a approximately 0.5 Mb tandem duplication in all the patients. The distal and proximal breakpoints were within an 80 and 130 kb region, respectively. This duplicated region contained a disrupted extra copy of the DACTYLIN gene and the entire LBX1 and beta-TRCP genes, known to be involved in limb development. The possible role of these genes in the SHFM3 phenotype is discussed.

Abnormalities, Multiple↗