In the current issue, Kuzmuk et al. offer a therapeutic option for patients with NPHS2 R138Q-associated nephrotic syndrome. For the first time in hereditary podocytopathies, this is offered by ...restoring the membrane targeting of a pathogenic protein. The idea that it is enough to liberate podocin from the trap of keratin 8, a key member of endoplasmic-reticulum–associated protein degradation complex, was brilliantly recognized based on former results obtained in cystic fibrosis.
The research of Mendel, born two centuries ago, still has many direct implications for our everyday clinical work. He introduced the terms “dominant” and “recessive” characters and determined their ...3:1 ratio in the offspring of heterozygous “hybrid” plants. This distribution allowed calculation of the number of the phenotype-determining “elements,” i.e., the alleles, and has been used ever since to prove the monogenic origin of a disorder. The Mendelian inheritance of monogenic kidney disorders is still of great help in distinguishing them from those with multifactorial origin in clinical practice. Inheritance of most monogenic kidney disorders fits to Mendel’s observations: the equal contribution of the two parents and the complete penetrance or the direct correlation between the frequency of the recessive character and the degree of inbreeding. Nevertheless, beyond the truth of these basic concepts, several observations have expanded their genetic characteristics. The extreme genetic heterogeneity, the pleiotropy of the causal genes and the role of modifiers in ciliopathies, the digenic inheritance and parental imprinting in some tubulopathies, and the incomplete penetrance and eventual interallelic interactions in podocytopathies, reflect this expansion. For all these reasons, the transmission pattern in a natural setting may depend not only on the “character” but also on the causal gene and the variant. Mendel’s passion for research combined with his modest personality and meticulous approach can still serve as an example in the work required to understand the non-Mendelian universe of genetics.
Induction of heat shock protein (HSP)72 protects against obesity-induced insulin resistance, but the underlying mechanisms are unknown. Here, we show that HSP72 plays a pivotal role in increasing ...skeletal muscle mitochondrial number and oxidative metabolism. Mice overexpressing HSP72 in skeletal muscle (HSP72Tg) and control wild-type (WT) mice were fed either a chow or high-fat diet (HFD). Despite a similar energy intake when HSP72Tg mice were compared with WT mice, the HFD increased body weight, intramuscular lipid accumulation (triacylglycerol and diacylglycerol but not ceramide), and severe glucose intolerance in WT mice alone. Whole-body VO2, fatty acid oxidation, and endurance running capacity were markedly increased in HSP72Tg mice. Moreover, HSP72Tg mice exhibited an increase in mitochondrial number. In addition, the HSP72 coinducer BGP-15, currently in human clinical trials for type 2 diabetes, also increased mitochondrial number and insulin sensitivity in a rat model of type 2 diabetes. Together, these data identify a novel role for activation of HSP72 in skeletal muscle. Thus, the increased oxidative metabolism associated with activation of HSP72 has potential clinical implications not only for type 2 diabetes but also for other disorders where mitochondrial function is compromised.
We aimed to identify incompletely penetrant (IP) variants and interallelic interactions in autosomal recessive disorders by a population‐genetic approach. Genotype and clinical data were collected ...from 9038 patients of European origin with ASL, ATP7B, CAPN3, CFTR, CTNS, DHCR7, GAA, GALNS, GALT, IDUA, MUT, NPHS1, NPHS2, PAH, PKHD1, PMM2, or SLC26A4‐related disorders. We calculated the relative allele frequency of each pathogenic variant (n = 1936) to the loss‐of‐function (LOF) variants of the corresponding gene in the patient (
A
C
p
t
V
/
A
C
p
t
L
O
F) and the general population (
AC
gnomAD
V
/
AC
gnomAD
LOF) and estimated the penetrance of each variant by calculating their ratio:
(
A
C
p
t
V
/
A
C
p
t
L
O
F
)
(
A
C
g
n
o
m
A
D
V
/
A
C
g
n
o
m
A
D
L
O
F
) (V/LOF ratio). We classified all variants as null or hypomorphic based on the associated clinical phenotype. We found 25 variants, 29% of the frequent 85 variants, to be underrepresented in the patient population (V/LOF ratio <30% with p < 7.22 × 10−5), including 22 novel ones in the ASL, CAPN3, CFTR, GAA, GALNS, PAH, and PKHD1 genes. In contrast to the completely penetrant variants (CP), the majority of the IP variants were hypomorphic (IP: 16/18, 88%; CP: 177/933, 19.0%; p = 5.12 × 10−10). Among them, only the NPHS2 R229Q variant was subject to interallelic interactions. The proposed algorithm identifies frequent IP variants and estimates their penetrance and interallelic interactions in large patient cohorts.
NPHS2, encoding podocin, is the major gene implicated in steroid‐resistant nephrotic syndrome. Its c.686G>A, p.R229Q variant is the first human variant with a mutation‐dependent pathogenicity; it is ...only pathogenic when trans‐associated to specific mutations. Secondary to its high allele frequency in the European, South Asian, African, and Latino populations, its benign trans‐associations can be accidentally identified in affected patients. Distinguishing pathogenic and benign p.R229Q associations can be challenging. In this paper, we present the currently known pathogenic and benign associations, and show that a rare p.R229Q association can be considered pathogenic if the variant in trans meets the following criteria; it affects the 270–351 residues and alters but does not disrupt the oligomerization, its p.R229Q association is found in a family with slowly progressing focal segmental glomerulosclerosis, but is expected to be rare in the general population (<1:106). We show that >15% of the p.R229Q associations identified so far in patients are benign.
The NPHS2 p.R229Q variant is pathogenic only when trans‐associated to specific mutations.
Secondary to its high allele frequency its benign trans‐associations can be accidentally identified in affected patients. We present the known pathogenic and benign associations, and show that a rare R229Q‐association can be considered pathogenic if the variant in trans affects the 270–351 residues and alters the oligomerization without disrupting it, its R229Q‐association is found in late‐onset FSGS, but is expected to be rare in the general population (<1:106).
Pseudouridylation is one of the most abundant RNA modifications in eukaryotes, making pseudouridine known as the “fifth nucleoside.” This highly conserved alteration affects all non-coding and coding ...RNA types. Its role and importance have been increasingly widely researched, especially considering that its absence or damage leads to serious hereditary diseases. Here, we summarize the human genetic disorders described to date that are related to the participants of the pseudouridylation process.
Monogenic disorders result from defects in a single gene. According to Mendel's laws, these disorders are inherited in either a recessive or dominant fashion. Autosomal-recessive disorders require a ...disease-causing variant on both alleles, and according to our current understanding, their pathogenicities are not influenced by each other. Here we present an autosomal-recessive disorder, nephrotic syndrome type 2 (MIM 600995), in which the pathogenicity of an NPHS2 allele encoding p.Arg229Gln depends on the trans-associated mutation. We show that, contrary to expectations, this allele leads to a disease phenotype only when it is associated specifically with certain 3' NPHS2 mutations because of an altered heterodimerization and mislocalization of the encoded p.Arg229Gln podocin. The disease-associated 3' mutations exert a dominant-negative effect on p.Arg229Gln podocin but behave as recessive alleles when associated with wild-type podocin. Therefore, the transmission rates for couples carrying the disease-associated mutations and p.Arg229Gln may be substantially different from those expected in autosomal-recessive disorders.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
We report on a sibling pair with the EPG5 c.1007A > G mutation who developed a severe form of Vici syndrome and died in infancy. The c.1007A > G (p.Gln336Arg) mutation, affecting the penultimate ...nucleotide and the splicing of exon 2 is the most common mutation of EPG5 and is typically associated with a less devastating prognosis: cardiomyopathy and cataract are less frequent consequences and the median survival time is 78 months compared to an overall median survival of 42 months. The less severe course related to c.1007A > G was formerly explained by the preserved canonical splicing in 25% of the transcripts. In contrast, we found the messenger RNA encoded by the c.1007A > G allele to be absent, explaining the severe course of the disease. This family provides another example of phenotypic variability related to a differential splicing.
Background
Autosomal recessive polycystic kidney disease (ARPKD) is genetically one of the least heterogeneous ciliopathies, resulting primarily from mutations of
PKHD1
. Nevertheless, 13–20% of ...patients diagnosed with ARPKD are found not to carry
PKHD1
mutations by sequencing. Here, we assess whether
PKHD1
copy number variations or second locus mutations explain these cases.
Methods
Thirty-six unrelated patients with the clinical diagnosis of ARPKD were screened for
PKHD1
point mutations and copy number variations. Patients without biallelic mutations were re-evaluated and screened for second locus mutations targeted by the phenotype, followed, if negative, by clinical exome sequencing.
Results
Twenty-eight patients (78%) carried
PKHD1
point mutations, three of whom on only one allele. Two of the three patients harbored in trans either a duplication of exons 33–35 or a large deletion involving exons 1–55. All eight patients without
PKHD1
mutations (22%) harbored mutations in other genes (
PKD1
(
n
= 2),
HNF1B
(
n
= 3),
NPHP1
,
TMEM67
,
PKD1
/
TSC2
). Perinatal respiratory failure, a kidney length > +4SD and early-onset hypertension increase the likelihood of
PKHD1
-associated ARPKD. A patient compound heterozygous for a second and a last exon truncating
PKHD1
mutation (p.Gly4013Alafs*25) presented with a moderate phenotype, indicating that fibrocystin is partially functional in the absence of its C-terminal 62 amino acids.
Conclusions
We found all ARPKD cases without
PKHD1
point mutations to be phenocopies, and none to be explained by biallelic
PKHD1
copy number variations. Screening for copy number variations is recommended in patients with a heterozygous point mutation.
Nephronophthisis, an autosomal recessive nephropathy, is responsible for 10% of childhood chronic renal failure. The deletion of its major gene, NPHP1, with a minor allele frequency of 0.24% in the ...general population, is the most common mutation leading to a monogenic form of childhood chronic renal failure. It is challenging to detect it in the heterozygous state. We aimed to evaluate the sensitivity and the specificity of the quantitative multiplex PCR of short fluorescent fragments (QMPSF) in its detection.
After setting up the protocol of QMPSF, we validated it on 39 individuals diagnosed by multiplex ligation-dependent probe amplification (MLPA) with normal NPHP1 copy number (n=17), with heterozygous deletion (n=13, seven parents and six patients), or with homozygous deletion (n=9). To assess the rate of the deletions that arise from independent events, deleted alleles were haplotyped.
The results of QMPSF and MLPA correlated perfectly in the identification of 76 heterozygously deleted and 56 homozygously deleted exons. The inter-experimental variability of the dosage quotient obtained by QMPSF was low: control, 1.05 (median; range, 0.86-1.33, n = 102 exons); heterozygous deletion, 0.51 (0.42-0.67, n = 76 exons); homozygous deletion, 0 (0-0, n = 56 exons). All patients harboring a heterozygous deletion were found to carry a hemizygous mutation. At least 15 out of 18 deletions appeared on different haplotypes and one deletion appeared de novo.
The cost- and time-effective QMPSF has a 100% sensitivity and specificity in the detection of NPHP1 deletion. The potential de novo appearance of NPHP1 deletions makes its segregation analysis highly recommended in clinical practice.
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