Autosomal Recessive Primary Microcephaly (MCPH): An Update

Zaqout, Sami; Morris-Rosendahl, Deborah J.; Kaindl, Angela M.

doi:10.1055/s-0037-1601448

Cited by 74 publications

(43 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Microcephaly, a congenital defect in which the head circumference is reduced due to a decrease in brain size, is the defining feature of autosomal recessive primary microcephaly (MCPH for microcephaly primary hereditary). MCPH can be caused by mutations in any of at least 17 genes and overlaps phenotypically and genetically with Seckel syndrome, which is characterized by short stature and craniofacial anomalies in addition to microcephaly (Zaqout et al, 2017). Many of the genes mutated in MCPH or Seckel syndrome encode centrosomal proteins involved in centriole duplication and mitotic spindle formation, such as CENPJ, CEP63, and ASPM (Nigg and Holland, 2018).…”

Section: Increased P53 Activity Contributes To the Developmental Defementioning

confidence: 99%

The role of p53 in developmental syndromes

Bowen

Attardi

2019

Journal of Molecular Cell Biology

View full text Add to dashboard Cite

While it is well appreciated that loss of the p53 tumor suppressor protein promotes cancer, growing evidence indicates that increased p53 activity underlies the developmental defects in a wide range of genetic syndromes. The inherited or de novo mutations that cause these syndromes affect diverse cellular processes, such as ribosome biogenesis, DNA repair, and centriole duplication, and analysis of human patient samples and mouse models demonstrates that disrupting these cellular processes can activate the p53 pathway. Importantly, many of the developmental defects in mouse models of these syndromes can be rescued by loss of p53, indicating that inappropriate p53 activation directly contributes to their pathogenesis. A role for p53 in driving developmental defects is further supported by the observation that mouse strains with broad p53 hyperactivation, due to mutations affecting p53 pathway components, display a host of tissue-specific developmental defects, including hematopoietic, neuronal, craniofacial, cardiovascular, and pigmentation defects. Furthermore, germline activating mutations in TP53 were recently identified in two human patients exhibiting bone marrow failure and other developmental defects. Studies in mice suggest that p53 drives developmental defects by inducing apoptosis, restraining proliferation, or modulating other developmental programs in a cell type-dependent manner. Here, we review the growing body of evidence from mouse models that implicates p53 as a driver of tissue-specific developmental defects in diverse genetic syndromes.

show abstract

Section: Increased P53 Activity Contributes To the Developmental Defementioning

confidence: 99%

The role of p53 in developmental syndromes

Bowen

Attardi

2019

Journal of Molecular Cell Biology

View full text Add to dashboard Cite

show abstract

“…These include microcephaly (2–5, 7–11, 15–21), intellectual disability (ID) (2–5, 10, 11, 19–22), speech delay (2, 3, 11, 16, 20), motor delay (3, 5, 16), spasticity (3, 7, 23), infantile spasm (3, 5), epilepsy (2–5, 7, 8, 11), behavior abnormalities (3, 4, 7, 11, 16), high-arched palate (3, 7, 16), dysmorphic face (3, 5, 11, 24), spastic quadriparesis (3, 7), micrognathia (3), dysconjugate gaze (25), and dysarthria (25). Brain imaging in these patients has variously revealed normal findings (26), simplified gyrus (2–5, 9, 10, 16, 20), pachygyria (2–5, 16), cortical thickening (2–5, 16), corpus callosum abnormalities (3–5, 7, 16), lissencephaly (2, 3, 11, 16, 20), schizencephaly (2–4, 16, 20), polymicrogyria (2–4, 16), and heterotopia (3, 4). In our patient, a simplified gyrus was observed alongside definite microcephaly, ID, and speech delay, which are all typical features of WDR62 mutation.…”

Section: Discussionmentioning

confidence: 99%

“…MCPH has previously been described as a genetically heterogeneous disorder influenced by mutations in at least 20 genes including ( MCPH1, WDR62, CDK5RAP2, KNL1, ASPM, CENPJ, STIL, CEP135, CEP152, ZNF335, PHC1, CDK6, CENPE, SASS6, MFSD2A, ANKLE2, CIT, AGMO, RTTN , and PGAP2 ) (2, 7). However, mutations in two particular genes are thought to be primarily responsible, with ASPM mutations being observed in over half of cases (1, 7, 8), and WDR62 mutations accounting for around 10% of MCPH cases (3, 5, 7, 8).…”

Section: Introductionmentioning

confidence: 99%

Two Novel Mutations (c.883-4_890del and c.1684C>G) of WDR62 Gene Associated With Autosomal Recessive Primary Microcephaly: A Case Report

Lee

Kim

et al. 2019

Front. Pediatr.

View full text Add to dashboard Cite

Background: Autosomal recessive primary microcephaly (Microcephaly Primary Hereditary, MCPH) is a rare disorder, affecting 1 in 10,000 children in areas where consanguineous marriages are common. WDR62 gene mutations are the second most common cause of MCPH. Herein, we report a case of primary microcephaly caused by two novel WDR62 mutations, which is, to our knowledge, the first such case report in East Asia.Case presentation: A 6-year-old girl visited our outpatient clinic as a result of microcephaly and delayed development. The patient was born at 36 weeks 4 days through cesarean section. Her birth weight was 1.8 kg (<1st percentile), and she was noted to have microcephaly (head circumference at birth was 28 cm, <−3SD). On examination, delayed speech development and microcephaly with an occipitofrontal head circumference of 43.5 cm (<−3SD) were noted. The patient's gross and fine motor development was normal. Her intelligence quotient was 43 (<0.1 percentile), the same as a 27-month-old child, and her social intelligence quotient was 76.92. Brain imaging revealed simplified gyral patterns of the cerebral cortex; however, laboratory findings, including organic acids, were normal. Multiplex ligation-dependent probe amplification technique for microdeletion syndrome and chromosomal microarray, showed no abnormality. Clinical exome sequencing test revealed two novel heterozygous variants in the WDR62 gene at two different sites: in the boundary of intron 7 and exon 8 (NM_001083961.1: c.883-4_890del) and in exon 13 (NM_001083961.1: c.1684C>G). The patient's parents were identified as heterozygous carriers for each variation.Conclusion: We report on two novel heterozygous mutations in East Asia. Our data expand the understanding of WDR62 mutations.

show abstract

“…CM can be the result of nongenetic conditions, such as viral infections and toxic exposure, or it can be generated by rare genetic disorders [25]. Primary hereditary microcephaly (MCPH) is the simplest form of genetic CM, in which brain size reduction is accompanied by grossly normal brain architecture and mild to moderate intellectual disability [25,27]. The association of severe microcephaly and proportionate body growth reduction is instead characteristic of Seckel syndrome (SCKS).…”

Section: Introductionmentioning

confidence: 99%

Precision Revisited: Targeting Microcephaly Kinases in Brain Tumors

Pallavicini

Berto

Cunto

2019

IJMS

View full text Add to dashboard Cite

Glioblastoma multiforme and medulloblastoma are the most frequent high-grade brain tumors in adults and children, respectively. Standard therapies for these cancers are mainly based on surgical resection, radiotherapy, and chemotherapy. However, intrinsic or acquired resistance to treatment occurs almost invariably in the first case, and side effects are unacceptable in the second. Therefore, the development of new, effective drugs is a very important unmet medical need. A critical requirement for developing such agents is to identify druggable targets required for the proliferation or survival of tumor cells, but not of other cell types. Under this perspective, genes mutated in congenital microcephaly represent interesting candidates. Congenital microcephaly comprises a heterogeneous group of disorders in which brain volume is reduced, in the absence or presence of variable syndromic features. Genetic studies have clarified that most microcephaly genes encode ubiquitous proteins involved in mitosis and in maintenance of genomic stability, but the effects of their inactivation are particularly strong in neural progenitors. It is therefore conceivable that the inhibition of the function of these genes may specifically affect the proliferation and survival of brain tumor cells. Microcephaly genes encode for a few kinases, including CITK, PLK4, AKT3, DYRK1A, and TRIO. In this review, we summarize the evidence indicating that the inhibition of these molecules could exert beneficial effects on different aspects of brain cancer treatment.

show abstract

Autosomal Recessive Primary Microcephaly (MCPH): An Update

Cited by 74 publications

References 41 publications

The role of p53 in developmental syndromes

The role of p53 in developmental syndromes

Two Novel Mutations (c.883-4_890del and c.1684C>G) of WDR62 Gene Associated With Autosomal Recessive Primary Microcephaly: A Case Report

Precision Revisited: Targeting Microcephaly Kinases in Brain Tumors

Contact Info

Product

Resources

About