Hallermann-Streiff syndrome: A missing molecular link for a highly recognizable syndrome

Schmidt, Julia; Wollnik, Bernd

doi:10.1002/ajmg.c.31668

Cited by 22 publications

(24 citation statements)

References 64 publications

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“…217 The clinical diagnosis of Hallermann-Streiff syndrome is particularly based on the characteristic craniofacial dysmorphism. 218 Mental development is not affected in most cases. 225,226,228,229 The C-terminal propeptide of FBN1 encoded by these exons is also called asprosin, a hormone regulating energy metabolism.…”

Section: Gapo Syndrome (Mim #230740)mentioning

confidence: 99%

“…Dental anomalies encompass neonatal and supernumerary teeth, but also absence or delayed eruption of teeth, and enamel hypoplasia 217 . The clinical diagnosis of Hallermann‐Streiff syndrome is particularly based on the characteristic craniofacial dysmorphism 218 . Mental development is not affected in most cases 216,219 .…”

Section: Pathogenesis and Clinical Phenotypes Of Selected Premature Amentioning

confidence: 99%

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Premature aging disorders: A clinical and genetic compendium

2020

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Progeroid disorders make up a heterogeneous group of very rare hereditary diseases characterized by clinical signs that often mimic physiological aging in a premature manner. Apart from Hutchinson-Gilford progeria syndrome, one of the bestinvestigated progeroid disorders, a wide spectrum of other premature aging phenotypes exist, which differ significantly in their clinical presentation and molecular pathogenesis. Next-generation sequencing (NGS)-based approaches have made it feasible to determine the molecular diagnosis in the early stages of a disease. Nevertheless, a broad clinical knowledge on these disorders and their associated symptoms is still fundamental for a comprehensive patient management and for the interpretation of variants of unknown significance from NGS data sets. This review provides a detailed overview on characteristic clinical features and underlying molecular genetics of well-known as well as only recently identified premature aging disorders and also highlights novel findings towards future therapeutic options. K E Y W O R D S characteristic clinical features, hereditary, premature aging, progeroid disorders 1 | INTRODUCTION Aging is a general biological phenomenon that affects all human beings and results in a functional decline of physiological systems accompanied by an increased risk for chronic ailments with advancing chronological age. 1,2 At the molecular level, aging is for example associated with genomic instability, loss of heterochromatin, and the accumulation of macromolecular damage leading to reduced (stem) cell function and tissue regeneration. 3 Progeroid disorders show many clinical features of aging-associated pathologies and signs similar to physiological aging; however, they occur at earlier ages and often progress rapidly. In many aspects progeria therefore represents a timelapse form of aging. Premature aging processes are mostly segmental in that they involve one or more organs, but do not exhibit all aspects associated with physiological aging. Premature aging signs include, among others, alopecia, hair graying, lipodystrophy, osteoporosis, joint contractures, cataract, hearing loss, atherosclerosis, cardiovascular diseases, diabetes mellitus and malignancies at an early age. In addition to these typical aging phenotypes, progeria patients may also present with growth retardation, developmental delay, and intellectual disability. A more modular view of segmental premature aging syndromes hypothesizes that a cluster of symptoms appearing in several disorders might be due to a common underlying cause-for example, alopecia, osteoporosis and nail atrophy have been proposed to be related to telomere shortening. 4 Research into premature aging disorders aims at understanding the pathogenesis and to develop novel treatment strategies, but also intends to unshadow physiological aging processes since premature aging phenotypes mirror many of the clinical aspects of physiological aging. 3 One of the best-known premature aging disorders is the Hutchinson-Gilford progeria syndr...

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Section: Gapo Syndrome (Mim #230740)mentioning

confidence: 99%

Section: Pathogenesis and Clinical Phenotypes Of Selected Premature Amentioning

confidence: 99%

Premature aging disorders: A clinical and genetic compendium

2020

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“…In their review, Schmidt and Wollnik make note of the heterogeneity in presentation of some clinical cases, yet there are many published patients with a highly recognizable or “classic” phenotype. The majority of the cases in the literature are sporadic, typically suggesting a de novo germline or mosaic cause for the disorder (Schmidt & Wollnick, ). Rarely, classically‐affected females have had children, and there has yet to be a convincing familial recurrence.…”

Section: Themes Of the Issuementioning

confidence: 52%

Unsolved recognizable patterns of human malformation: Challenges and opportunities

2018

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Due to the efforts of the clinical and scientific communities and boosted by recent advances in genetic technologies, we now understand the molecular mechanisms underlying most of the frequent and recognizable human malformation syndromes. However, some well‐established human malformation syndromes remain without a molecular diagnosis despite intensive investigation. This issue of Seminars mines the phenotypic entries in OMIM and estimates that of the documented 2,034 unsolved entries likely to represent a rare genetic disease, only 160 are well‐established and possibly amenable to investigation. This issue also reviews well‐characterized and extensively investigated human malformation syndromes and associations that remain unsolved, including the following: Dubowitz syndrome (MIM 223370%), Hallermann–Streiff syndrome (MIM 234100%), PHACE syndrome (MIM 606519), Oculocerebrocutaneous syndrome (MIM 164180), Aicardi syndrome (MIM 304050%), Gomez–Lopez–Hernandez syndrome and Rhombencephalosynapsis (MIM 601853%), VACTERL (MIM 192350%), and Nablus syndrome (MIM #608156). Possible explanations for their intractability to molecular diagnosis are explored, including genetic and phenotypic heterogeneity, mosaicism, epigenetics, gene–environment interactions, and other non‐Mendelian contributions. Finally, this issue of Seminars presents a path forward for these unsolved rare conditions and suggests a renewed focus on solving amendable OMIM disorders. It is clear that the way forward will require new technologies, global cooperation, and data sharing; these will also be necessary to help reach the vision of the International Rare Diseases Research Consortium (IRDiRC), that is to enable all people living with a rare disease to receive an accurate diagnosis, care and available therapy within 1 year of coming to medical attention.

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“…These lines were diploid and karyotypically stable, and could be differentiated into neural crest cells (NCCs) and spontaneously-contracting cardiomyocytes (CMs) with comparable efficiencies (Figs 1d,e and S1h,i). NCCs and CMs were chosen due to their relevance to this syndrome, since progressing cardiomyopathy is a recurrent HSS manifestation and it also invariably presents as a neurocristopathy 32 . Taken together, we now have a model to study the mechanisms underlying HSS, while also characterizing CHD6 in both a proliferative and a post-mitotic context.…”

Section: A Putatively-causative Hss Mutation and Generation Of Isogenmentioning

confidence: 99%

“…Due to its clinical course and progression, HSS is regarded as a premature aging disorder 29, 30,31 . With only few cases reported to date, and with virtually all reports being descriptive, there is an apparent need for dissecting the molecular pathways underlying HSS 32 . Given that in the only available mouse model for CHD6 lacking exon 12 (encoding its conserved ATPase domain) no obvious phenotype apart from mild ataxia is observed 21 , we chose to model this disease by generating isogenic induced pluripotent stem cell (iPSC) lines carrying or not the CHD6 mutation.…”

Section: Introductionmentioning

confidence: 99%

Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology

Kargapolova

Rehimi

Kayserli³

et al. 2020

Preprint

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Members of the chromodomain-helicase-DNA binding (CHD) protein family are chromatin remodelers critically implicated in human pathologies, with CHD6 being one of its least studied members. Here, we discovered a de novo CHD6 missense mutation in a patient clinically presenting the rare Hallermann-Streiff syndrome (HSS). We used genome editing to generate isogenic iPSC lines and model HSS in relevant cell types. We show that CHD6 binds a cohort of autophagy and stress response genes across cell types. The HSS-mutation affects CHD6 protein folding and impairs its ability to recruit co-factors in response to DNA damage or autophagy stimulation. This leads to an accumulation of DNA damage burden and to senescence-like phenotypes. By combining genomics and functional assays, we describe for the first time a molecular mechanism for the chromatin control of autophagic flux and genotoxic stress surveillance that applies broadly to human cell types and explains HSS onset.

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Hallermann-Streiff syndrome: A missing molecular link for a highly recognizable syndrome

Cited by 22 publications

References 64 publications

Premature aging disorders: A clinical and genetic compendium

Premature aging disorders: A clinical and genetic compendium

Unsolved recognizable patterns of human malformation: Challenges and opportunities

Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology

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