[show abstract][hide abstract] ABSTRACT: Context.IGSF1 deficiency was recently discovered as a novel X-linked cause of central hypothyroidism (CeH) and macroorchidism. However, clinical and biochemical data regarding growth, puberty, and metabolic outcome, as well as features of female carriers, are scarce.Objective.To investigate clinical and biochemical characteristics associated with IGSF1 deficiency in both sexes.Methods.All patients (n=42, 24 males) from 10 families examined in the university clinics of Leiden, Amsterdam, Cambridge, and Milan were included in this case series. Detailed clinical data were collected with an identical protocol and biochemical measurements were performed in a central laboratory.Results.Male patients (age 0-87 years, 17 index cases and 7 from family studies) showed CeH (100%), hypoprolactinemia (n=16, 67%) and transient partial growth hormone deficiency (GHD, n=3, 13%). Pubertal testosterone production was delayed, as were the growth spurt and pubic hair development. However, testicular growth started at a normal age and attained macroorchid size in all evaluable adults. BMI, fat percentage and waist circumference tended to be elevated. The metabolic syndrome was present in four out of five patients over 55 years. Heterozygous female carriers (age 32-80 years) showed CeH in 6 out of 18 cases (33%), hypoprolactinemia in 2 (11%), and GHD in none. As in men, BMI, fat percentage, and waist circumference were relatively high, and the metabolic syndrome was present in three cases.Conclusion.In males, the X-linked IGSF1 deficiency syndrome is characterized by CeH, hypoprolactinemia, delayed puberty, macroorchidism and increased body weight. A subset of female carriers also exhibits CeH.
The Journal of clinical endocrinology and metabolism 10/2013; · 6.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: Context:The first human cases (female 6yrs, male 47yrs and daughter 11yrs) with growth retardation/short stature, skeletal dysplasia, constipation and defective thyroid receptor alpha (TRα), have been recently described.Objective:A 45yr old short, overweight female with cognitive impairment, epilepsy and constipation was investigated.Design & Intervention:Clinical, biochemical and radiological assessment and THRA sequencing was undertaken. Her thyroid status, together with biochemical and physiological parameters, were evaluated at baseline and following thyroxine (T4) therapy.Results:The patient exhibits disproportionate short stature, macrocephaly, low FT4/FT3 ratio and reverse T3 levels, together with subnormal heart and basal metabolic rate (BMR). She is heterozygous for a novel frameshift/premature stop (Ala382ProfsX7) THRA mutation, generating a mutant TRα with constitutive corepressor binding and negligible coactivator recruitment, that inhibits its wild-type counterpart in a dominant-negative manner - both in vitro and in mutation-containing patient blood mononuclear cells studied ex vivo. Her alertness and constipation responded to thyroxine therapy, which readily suppressed TSH levels, raised BMR and normalised elevated muscle CK, but cardiac parameters (heart rate, contractility) remained relatively refractory. The patient, and a previous childhood case, showed reduced red cell mass with macrocytosis, unresponsive to T4 therapy.Conclusions:Clinical (short stature, macrocephaly, constipation) and biochemical (low FT4/FT3 ratio, subnormal reverse T3) findings that are congruent with previous cases and newly-recognised features (epilepsy) in this adult female with defective TRα, define a shared phenotype in TRα-mediated Resistance to Thyroid Hormone, with differential tissue responses to T4 treatment.
The Journal of clinical endocrinology and metabolism 08/2013; · 6.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: Short-rib polydactyly syndromes (SRPS I–V) are a group of lethal congenital disorders characterized by shortening of the ribs and long
bones, polydactyly, and a range of extraskeletal phenotypes. A number of other disorders in this grouping, including Jeune and Ellis-van
Creveld syndromes, have an overlapping but generally milder phenotype. Collectively, these short-rib dysplasias (with or without polydactyly)
share a common underlying defect in primary cilium function and form a subset of the ciliopathy disease spectrum. By using
whole-exome capture and massive parallel sequencing of DNA from an affected Australian individual with SRPS type III, we detected two
novel heterozygous mutations in WDR60, a relatively uncharacterized gene. These mutations segregated appropriately in the unaffected
parents and another affected family member, confirming compound heterozygosity, and both were predicted to have a damaging effect
on the protein. Analysis of an additional 54 skeletal ciliopathy exomes identified compound heterozygous mutations in WDR60 in a
Spanish individual with Jeune syndrome of relatively mild presentation. Of note, these two families share one novel WDR60 missense
mutation, although haplotype analysis suggested no shared ancestry. We further show that WDR60 localizes at the base of the primary cilium in wild-type human chondrocytes, and analysis of fibroblasts from affected individuals revealed a defect in ciliogenesis and aberrant accumulation of the GLI2 transcription factor at the centrosome or basal body in the absence of an obvious axoneme. These findings show that WDR60 mutations can cause skeletal ciliopathies and suggest a role for WDR60 in ciliogenesis.
The American Journal of Human Genetics 08/2013; · 11.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Thyroid hormone acts via receptor subtypes (TRα1, TRβ1, TRβ2) with differing tissue distributions, encoded by distinct genes (THRA, THRB). THRB mutations cause a disorder with central (hypothalamic-pituitary) resistance to thyroid hormone action with markedly elevated thyroid hormone and normal TSH levels. SCOPE OF REVIEW: This review describes the clinical features, genetic and molecular pathogenesis of a homologous human disorder mediated by defective THRA. Clinical features include growth retardation, skeletal dysplasia and constipation associated with low-normal T4 and high-normal T3 levels and a low T4/T3 ratio, together with subnormal reverse T3 levels. Heterozygous TRa1 mutations in affected individuals generate defective mutant receptors which inhibit wild-type receptor action in a dominant negative manner. MAJOR CONCLUSIONS: Mutations in human TRα1 mediate RTH with features of hypothyroidism in particular tissues (e.g. skeleton, gastrointestinal tract), but are not associated with a markedly dysregulated pituitary-thyroid axis. GENERAL SIGNIFICANCE: Human THRA mutations could be more common but may have eluded discovery due to the absence of overt thyroid dysfunction. Nevertheless, in the appropriate clinical context, a thyroid biochemical signature (low T4/T3 ratio, subnormal reverse T3 levels), may enable future identification of cases.
Biochimica et Biophysica Acta 03/2013; · 4.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: Intraflagellar transport (IFT) depends on two evolutionarily conserved modules, subcomplexes A (IFT-A) and B (IFT-B), to drive ciliary assembly and maintenance. All six IFT-A components and their motor protein, DYNC2H1, have been linked to human skeletal ciliopa-thies, including asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome), Sensenbrenner syndrome, and Mainzer-Saldino syndrome (MZSDS). Conversely, the 14 subunits in the IFT-B module, with the exception of IFT80, have unknown roles in human disease. To identify additional IFT-B components defective in ciliopathies, we independently performed different mutation analyses: candidate-based sequencing of all IFT-B-encoding genes in 1,467 individuals with a nephronophthisis-related ciliopathy or whole-exome resequencing in 63 individuals with ATD. We thereby detected biallelic mutations in the IFT-B-encoding gene IFT172 in 12 fam-ilies. All affected individuals displayed abnormalities of the thorax and/or long bones, as well as renal, hepatic, or retinal involvement, consistent with the diagnosis of ATD or MZSDS. Additionally, cerebellar aplasia or hypoplasia characteristic of Joubert syndrome was present in 2 out of 12 families. Fibroblasts from affected individuals showed disturbed ciliary composition, suggesting alteration of ciliary transport and signaling. Knockdown of ift172 in zebrafish recapitulated the human phenotype and demonstrated a genetic interaction between ift172 and ift80. In summary, we have identified defects in IFT172 as a cause of complex ATD and MZSDS. Our findings link the group of skeletal ciliopathies to an additional IFT-B component, IFT172, similar to what has been shown for IFT-A. Cilia are hair-like structures that project from the surface of most mammalian cells and are involved in diverse signaling pathways. Mutations in genes encoding ciliary
The American Journal of Human Genetics 01/2013; · 11.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Context: Mutations in DUOX2 gene have been associated with transient (tCH) or permanent congenital hypothyroidism (pCH) due to a dyshormonogenic defect. Objective: This study aimed to verify the prevalence of DUOX2 mutations and the associated clinical features in children selected by criteria supporting a partial iodide organification defect (PIOD). Patients and methods: Thirty children with PIOD-like criteria were enrolled and genotyped. A detailed clinical characterization was undertaken, together with the functional analysis of DUOX2 variations and the revision of the clinical and molecular data of the literature. Results: In this large selected series the prevalence of DUOX2 mutations was high (37%). We identified 12 missense variants, 1 splice-site, and 3 frameshift DUOX2 mutations. Functional analyses showed significant impairment of H2O2 generation with 5 missense variants. Stop-codon mutants were shown to totally abolish DUOX2 activity by nonsense-mediated RNA decay, exon skipping or protein truncation. DUOX2 mutations, either mono- or biallelic, were most frequently associated with permanent CH. Moreover, the present data suggested that, together with goiter and PIOD, the most significant features to select patients for DUOX2 analysis are the low fT4 and the high TSH concentrations at the first postnatal serum sampling, despite bordeline blood spot TSH. Interestingly, the analysis of previously described DUOX2 mutated cases confirmed the validity of these findings. Conclusions: The defects in the peroxide generation system are common among CH patients with PIOD. The most robust clinical parameters for selecting patients for DUOX2 analysis have been identified, and several DUOX2 variants have been functionally characterized.
The Journal of clinical endocrinology and metabolism 01/2013; · 6.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: Congenital central hypothyroidism occurs either in isolation or in conjunction with other pituitary hormone deficits. Using exome and candidate gene sequencing, we identified 8 distinct mutations and 2 deletions in IGSF1 in males from 11 unrelated families with central hypothyroidism, testicular enlargement and variably low prolactin concentrations. IGSF1 is a membrane glycoprotein that is highly expressed in the anterior pituitary gland, and the identified mutations impair its trafficking to the cell surface in heterologous cells. Igsf1-deficient male mice show diminished pituitary and serum thyroid-stimulating hormone (TSH) concentrations, reduced pituitary thyrotropin-releasing hormone (TRH) receptor expression, decreased triiodothyronine concentrations and increased body mass. Collectively, our observations delineate a new X-linked disorder in which loss-of-function mutations in IGSF1 cause central hypothyroidism, likely secondary to an associated impairment in pituitary TRH signaling.
[show abstract][hide abstract] ABSTRACT: Lipid accumulation in skeletal muscle and the liver is strongly implicated in the development of insulin resistance and type 2 diabetes, but the mechanisms underpinning fat accrual in these sites remain incompletely understood. Accumulating evidence of muscle mitochondrial dysfunction in insulin-resistant states has fuelled the notion that primary defects in mitochondrial fat oxidation may be a contributory mechanism. The purpose of our study was to determine whether patients with congenital lipodystrophy, a disorder primarily affecting white adipose tissue, manifest impaired mitochondrial oxidative phosphorylation in skeletal muscle.
Mitochondrial oxidative phosphorylation was assessed in quadriceps muscle using 31P-magnetic resonance spectroscopy measurements of phosphocreatine recovery kinetics after a standardized exercise bout in nondiabetic patients with congenital lipodystrophy and in age-, gender-, body mass index-, and fitness-matched controls.
The phosphocreatine recovery rate constant (k) was significantly lower in patients with congenital lipodystrophy than in healthy controls (P<0.001). This substantial (∼35%) defect in mitochondrial oxidative phosphorylation was not associated with significant changes in basal or sleeping metabolic rates.
Muscle mitochondrial oxidative phosphorylation is impaired in patients with congenital lipodystrophy, a paradigmatic example of primary adipose tissue dysfunction. This finding suggests that changes in mitochondrial oxidative phosphorylation in skeletal muscle could, at least in some circumstances, be a secondary consequence of adipose tissue failure. These data corroborate accumulating evidence that mitochondrial dysfunction can be a consequence of insulin-resistant states rather than a primary defect. Nevertheless, impaired mitochondrial fat oxidation is likely to accelerate ectopic fat accumulation and worsen insulin resistance.
The Journal of clinical endocrinology and metabolism 03/2012; 97(3):E438-42. · 6.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: Thyroid hormones exert their effects through alpha (TRα1) and beta (TRβ1 and TRβ2) receptors. Here we describe a child with classic features of hypothyroidism (growth retardation, developmental retardation, skeletal dysplasia, and severe constipation) but only borderline-abnormal thyroid hormone levels. Using whole-exome sequencing, we identified a de novo heterozygous nonsense mutation in a gene encoding thyroid hormone receptor alpha (THRA) and generating a mutant protein that inhibits wild-type receptor action in a dominant negative manner. Our observations are consistent with defective human TRα-mediated thyroid hormone resistance and substantiate the concept of hormone action through distinct receptor subtypes in different target tissues.
New England Journal of Medicine 12/2011; 366(3):243-9. · 51.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: Selenium, a trace element that is fundamental to human health, is incorporated into some proteins as selenocysteine (Sec), generating a family of selenoproteins. Sec incorporation is mediated by a multiprotein complex that includes Sec insertion sequence-binding protein 2 (SECISBP2; also known as SBP2). Here, we describe subjects with compound heterozygous defects in the SECISBP2 gene. These individuals have reduced synthesis of most of the 25 known human selenoproteins, resulting in a complex phenotype. Azoospermia, with failure of the latter stages of spermatogenesis, was associated with a lack of testis-enriched selenoproteins. An axial muscular dystrophy was also present, with features similar to myopathies caused by mutations in selenoprotein N (SEPN1). Cutaneous deficiencies of antioxidant selenoenzymes, increased cellular ROS, and susceptibility to ultraviolet radiation-induced oxidative damage may mediate the observed photosensitivity. Reduced levels of selenoproteins in peripheral blood cells were associated with impaired T lymphocyte proliferation, abnormal mononuclear cell cytokine secretion, and telomere shortening. Paradoxically, raised ROS in affected subjects was associated with enhanced systemic and cellular insulin sensitivity, similar to findings in mice lacking the antioxidant selenoenzyme glutathione peroxidase 1 (GPx1). Thus, mutation of SECISBP2 is associated with a multisystem disorder with defective biosynthesis of many selenoproteins, highlighting their role in diverse biological processes.
The Journal of clinical investigation 11/2010; 120(12):4220-35. · 15.39 Impact Factor
[show abstract][hide abstract] ABSTRACT: Resistance to thyroid hormone (RTH), a dominantly inherited disorder usually associated with mutations in thyroid hormone receptor beta (THRB), is characterized by elevated levels of circulating thyroid hormones (including thyroxine), failure of feedback suppression of thyrotropin, and variable tissue refractoriness to thyroid hormone action. Raised energy expenditure and hyperphagia are recognized features of hyperthyroidism, but the effects of comparable hyperthyroxinemia in RTH patients are unknown. Here, we show that resting energy expenditure (REE) was substantially increased in adults and children with THRB mutations. Energy intake in RTH subjects was increased by 40%, with marked hyperphagia particularly evident in children. Rates of muscle TCA cycle flux were increased by 75% in adults with RTH, whereas rates of ATP synthesis were unchanged, as determined by 13C/31P magnetic resonance spectroscopy. Mitochondrial coupling index between ATP synthesis and mitochondrial rates of oxidation (as estimated by the ratio of ATP synthesis to TCA cycle flux) was significantly decreased in RTH patients. These data demonstrate that basal mitochondrial substrate oxidation is increased and energy production in the form of ATP synthesis is decreased in the muscle of RTH patients and that resting oxidative phosphorylation is uncoupled in this disorder. Furthermore, these observations suggest that mitochondrial uncoupling in skeletal muscle is a major contributor to increased REE in patients with RTH, due to tissue selective retention of thyroid hormone receptor alpha sensitivity to elevated thyroid hormone levels.
The Journal of clinical investigation 03/2010; 120(4):1345-54. · 15.39 Impact Factor